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Diet anD exercise in cognitive Function anD neurological Diseases

Diet anD exercise in cognitive Function anD neurological Diseases

editors

taHira FarooQui anD aKHlaQ a FarooQui

Copyright copy 2015 by Wiley‐Blackwell All rights reserved

Published by John Wiley amp Sons Inc Hoboken New JerseyPublished simultaneously in Canada

No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording scanning or otherwise except as permitted under Section 107 or 108 of the 1976 United States Copyright Act without either the prior written permission of the Publisher or authorization through payment of the appropriate per‐copy fee to the Copyright Clearance Center Inc 222 Rosewood Drive Danvers MA 01923 (978) 750‐8400 fax (978) 750‐4470 or on the web at wwwcopyrightcom Requests to the Publisher for permission should be addressed to the Permissions Department John Wiley amp Sons Inc 111 River Street Hoboken NJ 07030 (201) 748‐6011 fax (201) 748‐6008 or online at httpwwwwileycomgopermissions

Limit of LiabilityDisclaimer of Warranty While the publisher and author have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose No warranty may be created or extended by sales representatives or written sales materials The advice and strategies contained herein may not be suitable for your situation You should consult with a professional where appropriate Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages including but not limited to special incidental consequential or other damages

For general information on our other products and services or for technical support please contact our Customer Care Department within the United States at (800) 762‐2974 outside the United States at (317) 572‐3993 or fax (317) 572‐4002

Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic formats For more information about Wiley products visit our web site at wwwwileycom

Library of Congress Cataloging‐in‐Publication Data

Diet and exercise in cognitive function and neurological diseases Tahira Farooqui and Akhlaq A Farooqui editors p cm Includes bibliographical references and index ISBN 978-1-118-84055-9 (cloth)I Farooqui Tahira editor II Farooqui Akhlaq A editor [DNLM 1 Brainndashphysiology 2 Agingndashphysiology 3 Cognitionndashphysiology 4 Diet 5 Exercise 6 Nervous System Diseases WL 300] RA645N87 6128ndashdc23

2014043911

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

Diet anD exercise in cognitive Function anD neurological Diseases

Diet anD exercise in cognitive Function anD neurological Diseases

editors

taHira FarooQui anD aKHlaQ a FarooQui

Copyright copy 2015 by Wiley‐Blackwell All rights reserved

Published by John Wiley amp Sons Inc Hoboken New JerseyPublished simultaneously in Canada

No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording scanning or otherwise except as permitted under Section 107 or 108 of the 1976 United States Copyright Act without either the prior written permission of the Publisher or authorization through payment of the appropriate per‐copy fee to the Copyright Clearance Center Inc 222 Rosewood Drive Danvers MA 01923 (978) 750‐8400 fax (978) 750‐4470 or on the web at wwwcopyrightcom Requests to the Publisher for permission should be addressed to the Permissions Department John Wiley amp Sons Inc 111 River Street Hoboken NJ 07030 (201) 748‐6011 fax (201) 748‐6008 or online at httpwwwwileycomgopermissions

Limit of LiabilityDisclaimer of Warranty While the publisher and author have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose No warranty may be created or extended by sales representatives or written sales materials The advice and strategies contained herein may not be suitable for your situation You should consult with a professional where appropriate Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages including but not limited to special incidental consequential or other damages

For general information on our other products and services or for technical support please contact our Customer Care Department within the United States at (800) 762‐2974 outside the United States at (317) 572‐3993 or fax (317) 572‐4002

Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic formats For more information about Wiley products visit our web site at wwwwileycom

Library of Congress Cataloging‐in‐Publication Data

Diet and exercise in cognitive function and neurological diseases Tahira Farooqui and Akhlaq A Farooqui editors p cm Includes bibliographical references and index ISBN 978-1-118-84055-9 (cloth)I Farooqui Tahira editor II Farooqui Akhlaq A editor [DNLM 1 Brainndashphysiology 2 Agingndashphysiology 3 Cognitionndashphysiology 4 Diet 5 Exercise 6 Nervous System Diseases WL 300] RA645N87 6128ndashdc23

2014043911

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

Diet anD exercise in cognitive Function anD neurological Diseases

editors

taHira FarooQui anD aKHlaQ a FarooQui

Copyright copy 2015 by Wiley‐Blackwell All rights reserved

Published by John Wiley amp Sons Inc Hoboken New JerseyPublished simultaneously in Canada

No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording scanning or otherwise except as permitted under Section 107 or 108 of the 1976 United States Copyright Act without either the prior written permission of the Publisher or authorization through payment of the appropriate per‐copy fee to the Copyright Clearance Center Inc 222 Rosewood Drive Danvers MA 01923 (978) 750‐8400 fax (978) 750‐4470 or on the web at wwwcopyrightcom Requests to the Publisher for permission should be addressed to the Permissions Department John Wiley amp Sons Inc 111 River Street Hoboken NJ 07030 (201) 748‐6011 fax (201) 748‐6008 or online at httpwwwwileycomgopermissions

Limit of LiabilityDisclaimer of Warranty While the publisher and author have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose No warranty may be created or extended by sales representatives or written sales materials The advice and strategies contained herein may not be suitable for your situation You should consult with a professional where appropriate Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages including but not limited to special incidental consequential or other damages

For general information on our other products and services or for technical support please contact our Customer Care Department within the United States at (800) 762‐2974 outside the United States at (317) 572‐3993 or fax (317) 572‐4002

Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic formats For more information about Wiley products visit our web site at wwwwileycom

Library of Congress Cataloging‐in‐Publication Data

Diet and exercise in cognitive function and neurological diseases Tahira Farooqui and Akhlaq A Farooqui editors p cm Includes bibliographical references and index ISBN 978-1-118-84055-9 (cloth)I Farooqui Tahira editor II Farooqui Akhlaq A editor [DNLM 1 Brainndashphysiology 2 Agingndashphysiology 3 Cognitionndashphysiology 4 Diet 5 Exercise 6 Nervous System Diseases WL 300] RA645N87 6128ndashdc23

2014043911

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

Copyright copy 2015 by Wiley‐Blackwell All rights reserved

Published by John Wiley amp Sons Inc Hoboken New JerseyPublished simultaneously in Canada

No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording scanning or otherwise except as permitted under Section 107 or 108 of the 1976 United States Copyright Act without either the prior written permission of the Publisher or authorization through payment of the appropriate per‐copy fee to the Copyright Clearance Center Inc 222 Rosewood Drive Danvers MA 01923 (978) 750‐8400 fax (978) 750‐4470 or on the web at wwwcopyrightcom Requests to the Publisher for permission should be addressed to the Permissions Department John Wiley amp Sons Inc 111 River Street Hoboken NJ 07030 (201) 748‐6011 fax (201) 748‐6008 or online at httpwwwwileycomgopermissions

Limit of LiabilityDisclaimer of Warranty While the publisher and author have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose No warranty may be created or extended by sales representatives or written sales materials The advice and strategies contained herein may not be suitable for your situation You should consult with a professional where appropriate Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages including but not limited to special incidental consequential or other damages

For general information on our other products and services or for technical support please contact our Customer Care Department within the United States at (800) 762‐2974 outside the United States at (317) 572‐3993 or fax (317) 572‐4002

Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic formats For more information about Wiley products visit our web site at wwwwileycom

Library of Congress Cataloging‐in‐Publication Data

Diet and exercise in cognitive function and neurological diseases Tahira Farooqui and Akhlaq A Farooqui editors p cm Includes bibliographical references and index ISBN 978-1-118-84055-9 (cloth)I Farooqui Tahira editor II Farooqui Akhlaq A editor [DNLM 1 Brainndashphysiology 2 Agingndashphysiology 3 Cognitionndashphysiology 4 Diet 5 Exercise 6 Nervous System Diseases WL 300] RA645N87 6128ndashdc23

2014043911

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

Dedicated to the Next GenerationTo make this world healthier and happier

ldquoIf we could give every individual the right amount of nourishment and exercise not too little and not too much we would have found the safest way to healthrdquo

mdashHippocrates 440BC

Contributors xi

Foreword Kirk I Erickson xv

Foreword Shin Murakami xvii

Preface Tahira Farooqui and Akhlaq A Farooqui xix

Acknowledgments xxi

1 Nutrition Genes and Neuroscience Implications for Development Health and Disease 1Margaret Joy Dauncey

2 Neurochemical Effects of Western Diet Consumption on Human Brain 15Akhlaq A Farooqui and Tahira Farooqui

3 Effect of Mediterranean Diet on Human Health in Seniors Relationship with Telomers 29Virginia Boccardi and Giuseppe Paolisso

4 Effect of a Mediterranean Diet on Mental and Physical Quality of Life 39Marialaura Bonaccio Giovanni de Gaetano and Licia Iacoviello

5 Ketogenic Diets for the Treatment of Neurologic Disease 47Christa W Habela and Eric H Kossoff

6 Levels of n‐3 Fatty Acids and their Metabolites in the Brain Their Impact on Brain Function and Neurological Disorders 59Akhlaq A Farooqui and Tahira Farooqui

7 Homocysteine Levels in Neurological Disorders 73Ahmed A Moustafa Doaa H Hewedi Abeer M Eissa Dorota Frydecka and Błazej Misiak

8 Table Salt and Dementia 83Surender R Neravetla and Shantanu R Neravetla

CoNTENTS

viii Contents

9 Contribution of Diet and Exercise in the Pathogenesis of Major Depression 93Adrian L Lopresti

10 Role of Diet and Exercise in Diabetic Retinopathy 105Mohammad Shamsul Ola Haseeb A Khan and Abdullah S Alhomida

11 The Effect of Western Diet on Cognition in Humans 111Heather M Francis and Richard J Stevenson

12 Role of Diet and Exercise in Intervention of Age‐Induced Impairments 123Kanti Bhooshan Pandey and Syed Ibrahim Rizvi

13 Hormesis and Cognitive Function An EvolutionaryAdaptive Arabesque Leading to Longevity 133Alistair VW Nunn Geoffrey W Guy and Jimmy D Bell

14 Polyphenols and Cognitive Function 143Edwin D Lephart

15 Prevention of Dementia Through Modifiable Risk Factors 163Patsri Srisuwan

16 Physical Exercise Improves Cognition in Brain Disorders Alzheimerrsquos Disease 175Trevor Archer and Danilo Garcia

17 Molecular Biochemical and Physiological Basis of Beneficial Actions of Exercise 183Undurti N Das

18 Beneficial Effects of Exercise and Cognitive Training on Cognitive Functions in older Adults Introduction of Smart Aging Studies 205Rui Nouchi and Ryuta Kawashima

19 Exercise and Cognitive Functions 213Bijli Nanda and S Manjunatha

20 Role of Sleep in Cognition Immunity and Disease and Its Interaction with Exercise 225Mark R Zielinski and Dmitry Gerashchenko

21 Effect of Forced and Voluntary Exercise on Neural Plasticity Mediated by Astrocytes 241Caren Bernardi Mario Roberto Generosi Brauner and Carlos Alberto Gonccedilalves

22 Effect of Exercise on the Aging Brain 253Bonita L Marks

23 The Effects of Exercise on Neuronal Survival 267Michael J Chen

24 Exercise and Cognitive Function in older Adults 279Nicola J Gates and Maria Fiatarone Singh

25 Research Issues and Clinical Implications of Exercise Effects in the Treatment of Depressive and Anxiety Disorders 295A Garrett Hazelton Richard Bloch and Sy Saeed

Contents ix

26 Exercise‐Induced Protection Against Aging and Neurodegenerative Diseases Role of Redox‐ and Mitochondrial‐Based Alterations 309Inecircs Marques‐Aleixo Estela Santos‐Alves Paula I Moreira Paulo J Oliveira Joseacute Magalhatildees and Antoacutenio Ascensatildeo

27 Exercise Neuroplasticity and Growth Factors in Adolescence 323Helios Pareja‐Galeano Sara Mayero and Fabiaacuten Sanchis‐Gomar

28 Summary Perspective and Direction for Future Studies 339Tahira Farooqui and Akhlaq A Farooqui

Index 349

Abdullah S Alhomida Department of Biochem-istry College of Science King Saud University Riyadh Saudi Arabia

Trevor Archer Department of Psychology University of Gothenburg Gothenburg Sweden Network for Empowerment and Well‐Being Gothenburg Sweden

Antoacutenio Ascensatildeo Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Jimmy D Bell Department of Life Sciences Clipstone Building University of Westminster London UK

Caren Bernardi Programa de Poacutes-Graduaccedilatildeo Ciecircncias da Reabilitaccedilatildeo Universidade Federal de Ciecircncias da Sauacutede de Porto Alegre Porto Alegre Brazil

Richard Bloch Department of Psychiatry and Behavioral Medicine Brody School of Medicine at East Carolina University Greenville NC USA

Virginia Boccardi Department of Internal Medicine Surgical Neurological Metabolic Disease and Geriatric Medicine Second University of Naples Naples Italy

Marialaura Bonaccio Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Mario Roberto Generosi Brauner Escola de Educaccedilatildeo Fiacutesica (ESEF) Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Michael J Chen Department of Biological Sciences California State University Los Angeles CA USA

Undurti N Das UND Life Sciences Federal Way WA USA

Margaret Joy Dauncey Wolfson College University of Cambridge Cambridge UK

Abeer M Eissa Psychogeriatric Research Center Department of Psychiatry School of Medicine Ain Shams University Cairo Egypt

Kirk I Erickson Department of Psychology University of Pittsburgh Pittsburgh PA USA

Akhlaq A Farooqui Department of Molecular and Cellular Biochemistry College of Medicine The Ohio State University Columbus OH USA

Tahira Farooqui Department of Molecular and Cellular Biochemistry College of Medicine The Ohio State University Columbus OH USA

CoNTRIBUToRS

xii Contributors

Heather M Francis School of Psychology Science Department University of New South Wales Sydney New South Wales Australia

Dorota Frydecka Department and Clinic of Psychiatry Wrocław Medical University Wrocław Poland

Giovanni de Gaetano Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Danilo Garcia Network for Empowerment and Well‐Being Gothenburg Sweden Center for Ethics Law and Mental Health University of Gothenburg Gothenburg Sweden

Nicola J Gates School of Psychiatry Centre for Healthy Brain Ageing (CheBA) University of New South Wales Sydney New South Wales Australia Brain and Mind Psychology Sydney New South Wales Australia

Dmitry Gerashchenko Department of Psychiatry Harvard Medical School and Veterans Affairs Boston Healthcare System West Roxbury MA USA

Carlos Alberto Gonccedilalves Programa de Poacutes- Graduaccedilatildeo Ciecircncias da Reabilitaccedilatildeo Universi-dade Federal de Ciecircncias da Sauacutede de Porto Alegre Porto Alegre Brazil Departamento de Bioquiacutemica Instituto de Ciecircncias Baacutesicas da Sauacutede Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Geoffrey W Guy GW Pharmaceuticals Porton Down Salisbury Wiltshire UK

Christa W Habela Division of Child Neurology Department of Neurology The Johns Hopkins School of Medicine Baltimore MD USA

A Garrett Hazelton Department of Psychiatry and Behavioral Medicine Brody School of Med-icine at East Carolina University Greenville NC USA

Doaa H Hewedi Psychogeriatric Research Center Department of Psychiatry School of Medicine Ain Shams University Cairo Egypt

Licia Iacoviello Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Ryuta Kawashima Smart Ageing International Research Centre Institute of Development Aging and Cancer Tohoku University Sendai Japan

Haseeb A Khan Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia

Eric H Kossoff Division of Child Neurology Department of Neurology The Johns Hopkins School of Medicine Baltimore MD USA

Edwin D Lephart Department of Physiology and Developmental Biology and The Neuroscience Center College of Life Sciences Brigham Young University Provo UT USA

Adrian l Lopresti School of Psychology and Exercise Science Murdoch University Murdoch Western Australia Australia

Joseacute Magalhatildees Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Inecircs Marques‐Aleixo Research Center in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Bonita L Marks Departments of Exercise and Sport Science Emergency Medicine and Allied Health Sciences University of North Carolina at Chapel Hill Chapel Hill NC USA

Sara Mayero Department of Psychiatry Hospital Moncloa Madrid Spain

Błazej Misiak Department and Clinic of Psychiatry Wrocław Medical University Wrocław Poland Department of Genetics Wrocław Medical University Wrocław Poland

Paula I Moreira Centre for Neuroscience and Cell Biology (CNC) UC‐BiotechBiocant Park University of Coimbra Cantanhede Portugal Institute of Physiology Faculty of Medicine University of Coimbra Coimbra Portugal

Ahmed A Moustafa School of Social Sciences and Psychology amp Marcs Institute for Brain and Behaviour University of Western Sydney Sydney New South Wales Australia

Shin Murakami Department of Basic Sciences College of Osteopathic Medicine Touro Univer-sity‐California Mare Island Vallejo CA USA

Bijli Nanda Department of Physiology School of Medical Sciences and Research Sharda University Greater Noida Uttar Pradesh India

Shantanu R Neravetla Medical Director Heart Health Now LLC Springfield OH USA

Contributors xiii

Surender R Neravetla Director Cardiac Surgery Springfield Regional Medical Center Spring-field OH USA Wright State University Dayton OH USA

Rui Nouchi Human and Social Response Research Division International Research Institute of Disaster Science Tohoku University Sendai Japan Smart Ageing International Research Centre Institute of Development Aging and Cancer Tohoku University Sendai Japan

Alistair VW Nunn School of Pharmacy Uni-versity of Reading Reading UK

Mohammad Shamsul ola Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia

Paulo J oliveira Centre for Neuroscience and Cell Biology (CNC) UC‐BiotechBiocant Park University of Coimbra Cantanhede Portugal

Kanti Bhooshan Pandey Department of Biochemistry University of Allahabad Allahabad Uttar Pradesh India

Giuseppe Paolisso Department of Internal Medi-cine Surgical Neurological Metabolic Dis-ease and Geriatric Medicine Second University of Naples Naples Italy

Helios Pareja‐Galeano Department of Physiology School of Medicine University of Valencia Valencia Spain Fundacioacuten del Hospital Cliacutenico Universitario Valencia (FIHCUV‐ INCLIVA) Valencia Spain

Syed Ibrahim Rizvi Department of Biochemistry University of Allahabad Allahabad Uttar Pradesh India

Sy Saeed Department of Psychiatry and Behavioral Medicine Brody School of Medicine at East Carolina University Greenville NC USA

Fabiaacuten Sanchis‐Gomar Department of Physiology School of Medicine University of Valencia Valencia Spain Fundacioacuten del Hospital Cliacutenico Universitario Valencia (FIHCUV‐INCLIVA) Valencia Spain

Estela Santos‐Alves Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

S Manjunatha Endocrine Research Unit Mayo Clinic College of Medicine Rochester MN USA

Maria Fiatarone Singh Exercise Health and Performance Faculty Research Group Sydney Medical School The University of Sydney Lid-combe New South Wales Australia Hebrew SeniorLife Boston MA USA Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University Boston MA USA

Patsri Srisuwan Outpatient and Family Medicine Department Phramongkutklao Hospital and College of Medicine Bangkok Thailand

Richard J Stevenson Department of Psychology Macquarie University Sydney New South Wales Australia

Mark R Zielinski Department of Psychiatry Harvard Medical School and Veterans Affairs Boston Healthcare System West Roxbury MA USA

FoREWoRD

the brain is a plastic organ that is continuously changing and adapting to its environment because of this natural capacity for plasticity there has been an increasing interest from both scientific and public policy groups to attempt to leverage brain plasticity to prevent or treat neurological and psy-chiatric conditions From this perspective there have emerged three categories of treatments that attempt to take advantage of brain plasticity First there are traditional pharmaceutical treatments that try to manipulate the molecular milieu of the brain through medication thereby influencing the prevalence and trajectory of brain disorders unfortunately effective pharmaceutical treatments with minimal side effects and high compliance rates have remained elusive for many disorders of the brain thus in contrast to pharmaceutical approaches the other two approaches are nonphar-maceutical in nature and include (1) behavioral therapies (eg cognitive behavioral therapy) and (2) lifestyle changes (eg exercise habits) these two approaches are often referred to as ldquononpharmaceuti-calrdquo in the sense that they are not medication based However the term ldquononpharmaceuticalrdquo should not be confused with ldquononpharmacologicalrdquo indeed behavioral and lifestyle treatments are methods of manipulating the endogenous pharmacology of the brain

over the past decade there has been an explosion of scientific interest in ldquononpharmaceuticalrdquo approaches to brain plasticity especially those

approaches that include lifestyles (eg exercise habits) this body of work emerges within the context of a well‐established research demonstrating the impact of health behaviors on the function and integrity of visceral organs and physical health Amazingly it has been only relatively recently that the brain and its functions (eg cognition) have been considered as being closely linked to health behaviors such as physical activity and dietary habits indeed as the chapters in this book discuss the brain and its functions are highly susceptible to the same types of decay and dysfunction from engagement in unhealthy lifestyles as the rest of the body Fortunately massive amounts of research have now clearly demonstrated the importance of dietary and exercise habits with cognitive and brain function or diseases and suggest that these effects of unhealthy behaviors on the brain are modifiable For example the work by our group found that engagement in moderate‐intensity exercise several days a week for 1 year was sufficient for increasing the size of the hippocampus in a sample of cognitively healthy but sedentary elderly [1] interestingly the change in hippocampal volume was correlated with changes in spatial memory performance for the exercise group and not for the control group indicating that the changes in hippocampal volume were not a mean-ingless by‐product of greater exercise participation but rather that they had significant implications for cognitive function such findings indicate not only that the brain remains plastic but also that

xvi Foreword

engagement in exercise has the capability of modi-fying the structural integrity of the brain Many other studies have also reported similar effects of exercise physical activity and fitness on biomarkers brain health and cognitive function

As will be described throughout this book despite some consensus on the importance of exercise and dietary lifestyles for brain function there remains debate about the mechanisms the dosendashresponse and the extent to which these life-style choices are effective for both primary and secondary prevention of disease and long‐term treatment for the attenuation of cognitive or brain losses it will be necessary for well‐controlled randomized trials and longitudinal studies with larger sample sizes to more conclusively link these lifestyle approaches to improvements in cognitive and brain health Yet despite this need there is a growing consensus that dietary and exercise habits are important modifiable behaviors that directly influence cognitive and brain health throughout the lifespan the focus of this book titled Diet and

Exercise in Cognitive Function and Neurological Diseases addresses these topics and presents a timely and comprehensive review from world experts in neuroscience epidemiology neurology cognitive psychology nutrition genetics and exercise science this book will provide an excel-lent resource for students and researchers and serve as a guide for the development of future research projects and for the integration of health behaviors into clinical practice and public policies that strive to enhance cognitive and brain health

REFERENCE

1 erickson Ki et al exercise training increases size of hippocampus and improves memory Proc Natl Acad Sci U S A 2011 108(7) pp 3017ndash22

Kirk i erickson

Department of Psychology University of Pittsburgh

Pittsburgh PA USA

this is my warm welcome to the world of ldquodiet and exercise in cognitive function and neurological diseasesrdquo eating food and exercise are two fundamental activities in animal species they use three macronutrients for energy including carbohy-drates proteins and fatty acids Although the world Health organization (wHo) prioritizes ldquostopping hungerrdquo as a highest priority overnu-trition clearly is a concern on numerous health problems in the united states our body does not have positive mechanisms to remove overnu-trition which is why exercise has been a major intervention in order to reduce energy that is taken too much

the central nervous system (Cns) is a hungry tissue for energy it needs energy for a wide variety of functions and therefore when metabolic path-ways are altered Cns is in a big trouble in diabetes high glucose in the blood is characteristic due to deficits in insulin or insulin pathways the Alzheimerrsquos disease (Ad) which is a major cause of dementia shares characteristics of diabetes in the brainmdashit has been proposed to be classified as ldquotype 3 diabetesrdquo in Ad some neurons cannot take glucose inside as well as cannot use the secondary energy source neither with abundant glucose the body thinks why we should use the second energy source ketone bodies (and it does not use ketone

bodies) to turn the situation better glucose levels should be lower so that the neurons start to use ketone bodies

in Ad and some neurological diseases reducing glucose seems to be an effective strategy to provide the secondary energy to the neurons Low‐carbohydrate (low‐carb) diet has a direct effect on reducing glucose and importantly reducing insulin we now know reducing iGF‐1insulin signal can extend lifespan in a wide variety of species from worms to flies and to mammals Low‐carb diet may have a beneficial effect on extending lifespan

Ketogenic diet uses low carb to reduce glucose and high lipids to provide ketone bodies which is a promising treatment in the future Ketogenic diet has originally been used for the treatment of a neurological disease epilepsy However it needs a caution about complex effects of lipids some of which have negative effects on patients with cardiovascular diseases it is essential to shift the diet strategy to the lipids that have neutral or beneficial effects on the health Applications of the diet to diabetes and Ad have been considered

this book will provide a nicely blended over-view of diet and exercise it has chapters describing various types of diet including among

FoREWoRD

xviii Foreword

others ketogenic diet Mediterranean diet and n‐3 (omega‐3) diet other chapters describe a wide variety of benefits on exercise some toxic nutritional metabolites are also getting attention including homocysteine which is linked to methi-onine metabolism Methionine together with folic acidvitamin b12 has been implicated to play a role in normal aging

i would like to thank the editors for the opportunity to write Foreword of this exciting book

shin Murakami Phd

Department of Basic Sciences College of Osteopathic Medicine

Touro University California Vallejo CA USA

Diet and exercise play an important role in maintaining good cognitive function and longevity Macro‐ and micronutrients not only provide energy and building material to the body but also have ability to prevent and protect against age‐related neurological disor-ders Exercise initiates the maintenance of good cardiorespiratory cardiovascular cerebrovascular and muscular fitness by increasing energy con-sumption improving insulin sensitivity increasing blood flow increasing the expression of brain‐derived neurotrophic factor and reducing inflammation Western diet which is enriched in refined carbohy-drates (simple sugars) partially hydrogenated oils (peanut corn soybean and canola) and proteins of animal origin (enriched in corn‐based livestock) is high in salt and low in fiber At present in Western diet the ratio of arachidonic acid (ARA) to docosa-hexaenoic acid (DHA) is about 201 By contrast the Paleolithic diet (stone‐age diet) on which our forefathers lived and survived throughout their his-tory contained high amounts of fresh fruits green vegetables lean meats fish seeds piths and barks with ARA to DHA ratio of 11 Long‐term con-sumption of Western diet produces detrimental effect on health not only by inducing an increase in systemic and brain inflammation and oxidative stress through the stimulation of insulin‐like growth factor 1 (IGF‐1) and Toll‐like receptors and generation of high levels of ARA‐derived lipid mediators but also by mediating abnormalities in mitochondrial function along with the induction of

insulin resistance and leptin resistance in visceral organs and the brain The onset and induction of oxidative stress neuroinflammation and abnormal-ities in mitochondrial function are closely associated with impairments in frontal limbic and hippocampal systems leading to changes in learning memory cognition and hedonics In visceral tissues oxidative stress and inflammation along with genetic and environmental factors promote obesity diabetes metabolic syndrome heart disease and cancer These pathological conditions are risk factors for neurological disorders (stroke AD and depression) Thus incidences of neurological disorders are two‐ to threefold higher in patients with type 2 diabetes metabolic syndrome and cardiovascular diseases compared to normal subjects of the same age

The Mediterranean diet which is enriched in fruits vegetables garlic legumes and unrefined cereals and has moderate amount of fish and high amount of olive oil along with modest intake of red wine produces anti‐inflammatory antioxidant and antidiabetic effects leading to cardio‐ and neuroprotection in heart disease and neurological disorders

Exercise initiates the maintenance of good car-diorespiratory cardiovascular cerebrovascular and muscular fitness by preventing metabolic imbalance increasing energy consumption improving insulin sensitivity increasing blood flow elevating levels of brain‐derived neurotrophic factor reducing inflammation and enhancing learning and memory

PREFACE

xx PREFACE

Good nutrition daily exercise and adequate sleep are the foundations for maintaining optimal health

Information on diet and exercise is scattered throughout the literature in the form of original papers reviews and some books These books describe the effects of diet and exercise on visceral organs The purpose of this edited book is to pro-vide readers with a comprehensive and cutting‐edge information on the effects of diet and exercise on cognitive function and age‐related visceral and brain diseases in a manner which is useful not only to students and teachers but also to researchers dietitians nutritionists exercise physiologists and physicians To the best of our knowledge this edited book will be the first to provide a comprehensive description of signal transduction processes associated with the effects of diet and exercise on the cognitive function

This edited book has 28 chapters Chapters 1ndash9 describe the effects of various diet patterns on metabolic changes in visceral organs and the brain Chapters 10ndash26 provide information on the effects of diet and exercise on cognitive function and age‐related neurological disorders Chapter 27 deals

with the role of salt in the pathogenesis of dementia and stroke Finally Chapter 28 deals with perspective on the current progress that will be important for future studies on the effects of diet and exercise on cognitive function in normal subjects and age‐related neurological disorders

Our contributors have tried to ensure uniformity and mode of presentation simple and we have made sure that the progression of subject matter from one topic to another is logical Each chapter provides an extensive bibliography for readers to consult For the sake of simplicity and uniformity a large number of figures with chemical structures of metabolites along with line diagrams of colored signal transduction pathways are included We hope that our attempt to integrate and consolidate the knowledge on the effects of diet and exercise on cognitive function will initiate more studies on molecular mechanisms that link among diet and exercise with cognitive function in normal subjects and patients with age‐related neu-rological disorders

Tahira Farooqui Akhlaq A Farooqui

We thank all the authors of this book who shared their expertise by contributing chapters of a high standard thus making our editorial task much easier We are grateful to Justin Jeffryes Editorial Director at Wiley‐Blackwell for his cooperation and patience during this process We are also

thankful to Stephanie Dollan Senior Editorial Assistant at Wiley‐Blackwell for her professional handling of the manuscript

Tahira FarooquiAkhlaq A Farooqui

ACKNOWLEDGMENTS

Diet and Exercise in Cognitive Function and Neurological Diseases First Edition Edited by Tahira Farooqui and Akhlaq A Farooqui copy 2015 John Wiley amp Sons Inc Published 2015 by John Wiley amp Sons Inc

11 INTRODUCTION

Nutritionndashgene interactions play a pivotal role in cognitive function and neurological disease throughout life Nutrition is one of many environ-mental factors that profoundly alter the phenotypic expression of a given genotype with major impli-cations for development metabolism health and disease [1ndash4] These effects are mediated by changes in expression of multiple genes and can involve epigenetic mechanisms nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence Responses to nutrition are in turn affected by individual genetic variability The effects of nutrition on gene expression are exerted throughout the life cycle with prenatal and early postnatal life being especially critical periods for optimal development Changes in gene expression may be dynamic and short term stable and long term and even heritable between cell divisions and across generations

This review focuses on the following key topics First a short overview is provided on the role of nutrition in cognitive neuroscience Second mecha-nisms underlying nutritionndashgene interactions are discussed especially in relation to the roles of epige-netics and genetic variability in neuroscience

Third attention is focused on the importance of environment and epigenetics in neurological health and disease Finally the role of early nutrition in brain development and later neurological disease is addressed Overall this review highlights the criti-cal importance of nutritionndashgene interactions to optimal neurological function and prevention and treatment of multiple neurological disorders

12 NUTRITION AND COGNITIVE NEUROSCIENCE

The role of nutrition in cognitive neuroscience is highly complex because as with all aspects of nutrition it is multifactorial It is not concerned simply with the impact of a single chemical on the brain but with numerous interactions between multiple nutrients metabolites food and other environmental and genetic factors Nevertheless considerable evidence now links many aspects of nutrition with cognition mental health and well‐being neurological dysfunction and disease [1ndash9] Protective roles are suggested for the Mediterranean diet optimal energy status fish fruits vegetables polyphenols omega‐3 polyunsaturated fatty acids iron zinc copper and numerous vitamins

NUTRITION GENES AND NEUROSCIENCE IMPLICATIONS FOR DEVELOPMENT HEALTH AND DISEASE

Margaret Joy DaunceyWolfson College University of Cambridge Cambridge UK

1

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

ldquoIf we could give every individual the right amount of nourishment and exercise not too little and not too much we would have found the safest way to healthrdquo

mdashHippocrates 440BC

Contributors xi

Foreword Kirk I Erickson xv

Foreword Shin Murakami xvii

Preface Tahira Farooqui and Akhlaq A Farooqui xix

Acknowledgments xxi

1 Nutrition Genes and Neuroscience Implications for Development Health and Disease 1Margaret Joy Dauncey

2 Neurochemical Effects of Western Diet Consumption on Human Brain 15Akhlaq A Farooqui and Tahira Farooqui

3 Effect of Mediterranean Diet on Human Health in Seniors Relationship with Telomers 29Virginia Boccardi and Giuseppe Paolisso

4 Effect of a Mediterranean Diet on Mental and Physical Quality of Life 39Marialaura Bonaccio Giovanni de Gaetano and Licia Iacoviello

5 Ketogenic Diets for the Treatment of Neurologic Disease 47Christa W Habela and Eric H Kossoff

6 Levels of n‐3 Fatty Acids and their Metabolites in the Brain Their Impact on Brain Function and Neurological Disorders 59Akhlaq A Farooqui and Tahira Farooqui

7 Homocysteine Levels in Neurological Disorders 73Ahmed A Moustafa Doaa H Hewedi Abeer M Eissa Dorota Frydecka and Błazej Misiak

8 Table Salt and Dementia 83Surender R Neravetla and Shantanu R Neravetla

CoNTENTS

viii Contents

9 Contribution of Diet and Exercise in the Pathogenesis of Major Depression 93Adrian L Lopresti

10 Role of Diet and Exercise in Diabetic Retinopathy 105Mohammad Shamsul Ola Haseeb A Khan and Abdullah S Alhomida

11 The Effect of Western Diet on Cognition in Humans 111Heather M Francis and Richard J Stevenson

12 Role of Diet and Exercise in Intervention of Age‐Induced Impairments 123Kanti Bhooshan Pandey and Syed Ibrahim Rizvi

13 Hormesis and Cognitive Function An EvolutionaryAdaptive Arabesque Leading to Longevity 133Alistair VW Nunn Geoffrey W Guy and Jimmy D Bell

14 Polyphenols and Cognitive Function 143Edwin D Lephart

15 Prevention of Dementia Through Modifiable Risk Factors 163Patsri Srisuwan

16 Physical Exercise Improves Cognition in Brain Disorders Alzheimerrsquos Disease 175Trevor Archer and Danilo Garcia

17 Molecular Biochemical and Physiological Basis of Beneficial Actions of Exercise 183Undurti N Das

18 Beneficial Effects of Exercise and Cognitive Training on Cognitive Functions in older Adults Introduction of Smart Aging Studies 205Rui Nouchi and Ryuta Kawashima

19 Exercise and Cognitive Functions 213Bijli Nanda and S Manjunatha

20 Role of Sleep in Cognition Immunity and Disease and Its Interaction with Exercise 225Mark R Zielinski and Dmitry Gerashchenko

21 Effect of Forced and Voluntary Exercise on Neural Plasticity Mediated by Astrocytes 241Caren Bernardi Mario Roberto Generosi Brauner and Carlos Alberto Gonccedilalves

22 Effect of Exercise on the Aging Brain 253Bonita L Marks

23 The Effects of Exercise on Neuronal Survival 267Michael J Chen

24 Exercise and Cognitive Function in older Adults 279Nicola J Gates and Maria Fiatarone Singh

25 Research Issues and Clinical Implications of Exercise Effects in the Treatment of Depressive and Anxiety Disorders 295A Garrett Hazelton Richard Bloch and Sy Saeed

Contents ix

26 Exercise‐Induced Protection Against Aging and Neurodegenerative Diseases Role of Redox‐ and Mitochondrial‐Based Alterations 309Inecircs Marques‐Aleixo Estela Santos‐Alves Paula I Moreira Paulo J Oliveira Joseacute Magalhatildees and Antoacutenio Ascensatildeo

27 Exercise Neuroplasticity and Growth Factors in Adolescence 323Helios Pareja‐Galeano Sara Mayero and Fabiaacuten Sanchis‐Gomar

28 Summary Perspective and Direction for Future Studies 339Tahira Farooqui and Akhlaq A Farooqui

Index 349

Abdullah S Alhomida Department of Biochem-istry College of Science King Saud University Riyadh Saudi Arabia

Trevor Archer Department of Psychology University of Gothenburg Gothenburg Sweden Network for Empowerment and Well‐Being Gothenburg Sweden

Antoacutenio Ascensatildeo Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Jimmy D Bell Department of Life Sciences Clipstone Building University of Westminster London UK

Caren Bernardi Programa de Poacutes-Graduaccedilatildeo Ciecircncias da Reabilitaccedilatildeo Universidade Federal de Ciecircncias da Sauacutede de Porto Alegre Porto Alegre Brazil

Richard Bloch Department of Psychiatry and Behavioral Medicine Brody School of Medicine at East Carolina University Greenville NC USA

Virginia Boccardi Department of Internal Medicine Surgical Neurological Metabolic Disease and Geriatric Medicine Second University of Naples Naples Italy

Marialaura Bonaccio Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Mario Roberto Generosi Brauner Escola de Educaccedilatildeo Fiacutesica (ESEF) Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Michael J Chen Department of Biological Sciences California State University Los Angeles CA USA

Undurti N Das UND Life Sciences Federal Way WA USA

Margaret Joy Dauncey Wolfson College University of Cambridge Cambridge UK

Abeer M Eissa Psychogeriatric Research Center Department of Psychiatry School of Medicine Ain Shams University Cairo Egypt

Kirk I Erickson Department of Psychology University of Pittsburgh Pittsburgh PA USA

Akhlaq A Farooqui Department of Molecular and Cellular Biochemistry College of Medicine The Ohio State University Columbus OH USA

Tahira Farooqui Department of Molecular and Cellular Biochemistry College of Medicine The Ohio State University Columbus OH USA

CoNTRIBUToRS

xii Contributors

Heather M Francis School of Psychology Science Department University of New South Wales Sydney New South Wales Australia

Dorota Frydecka Department and Clinic of Psychiatry Wrocław Medical University Wrocław Poland

Giovanni de Gaetano Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Danilo Garcia Network for Empowerment and Well‐Being Gothenburg Sweden Center for Ethics Law and Mental Health University of Gothenburg Gothenburg Sweden

Nicola J Gates School of Psychiatry Centre for Healthy Brain Ageing (CheBA) University of New South Wales Sydney New South Wales Australia Brain and Mind Psychology Sydney New South Wales Australia

Dmitry Gerashchenko Department of Psychiatry Harvard Medical School and Veterans Affairs Boston Healthcare System West Roxbury MA USA

Carlos Alberto Gonccedilalves Programa de Poacutes- Graduaccedilatildeo Ciecircncias da Reabilitaccedilatildeo Universi-dade Federal de Ciecircncias da Sauacutede de Porto Alegre Porto Alegre Brazil Departamento de Bioquiacutemica Instituto de Ciecircncias Baacutesicas da Sauacutede Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Geoffrey W Guy GW Pharmaceuticals Porton Down Salisbury Wiltshire UK

Christa W Habela Division of Child Neurology Department of Neurology The Johns Hopkins School of Medicine Baltimore MD USA

A Garrett Hazelton Department of Psychiatry and Behavioral Medicine Brody School of Med-icine at East Carolina University Greenville NC USA

Doaa H Hewedi Psychogeriatric Research Center Department of Psychiatry School of Medicine Ain Shams University Cairo Egypt

Licia Iacoviello Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Ryuta Kawashima Smart Ageing International Research Centre Institute of Development Aging and Cancer Tohoku University Sendai Japan

Haseeb A Khan Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia

Eric H Kossoff Division of Child Neurology Department of Neurology The Johns Hopkins School of Medicine Baltimore MD USA

Edwin D Lephart Department of Physiology and Developmental Biology and The Neuroscience Center College of Life Sciences Brigham Young University Provo UT USA

Adrian l Lopresti School of Psychology and Exercise Science Murdoch University Murdoch Western Australia Australia

Joseacute Magalhatildees Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Inecircs Marques‐Aleixo Research Center in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Bonita L Marks Departments of Exercise and Sport Science Emergency Medicine and Allied Health Sciences University of North Carolina at Chapel Hill Chapel Hill NC USA

Sara Mayero Department of Psychiatry Hospital Moncloa Madrid Spain

Błazej Misiak Department and Clinic of Psychiatry Wrocław Medical University Wrocław Poland Department of Genetics Wrocław Medical University Wrocław Poland

Paula I Moreira Centre for Neuroscience and Cell Biology (CNC) UC‐BiotechBiocant Park University of Coimbra Cantanhede Portugal Institute of Physiology Faculty of Medicine University of Coimbra Coimbra Portugal

Ahmed A Moustafa School of Social Sciences and Psychology amp Marcs Institute for Brain and Behaviour University of Western Sydney Sydney New South Wales Australia

Shin Murakami Department of Basic Sciences College of Osteopathic Medicine Touro Univer-sity‐California Mare Island Vallejo CA USA

Bijli Nanda Department of Physiology School of Medical Sciences and Research Sharda University Greater Noida Uttar Pradesh India

Shantanu R Neravetla Medical Director Heart Health Now LLC Springfield OH USA

Contributors xiii

Surender R Neravetla Director Cardiac Surgery Springfield Regional Medical Center Spring-field OH USA Wright State University Dayton OH USA

Rui Nouchi Human and Social Response Research Division International Research Institute of Disaster Science Tohoku University Sendai Japan Smart Ageing International Research Centre Institute of Development Aging and Cancer Tohoku University Sendai Japan

Alistair VW Nunn School of Pharmacy Uni-versity of Reading Reading UK

Mohammad Shamsul ola Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia

Paulo J oliveira Centre for Neuroscience and Cell Biology (CNC) UC‐BiotechBiocant Park University of Coimbra Cantanhede Portugal

Kanti Bhooshan Pandey Department of Biochemistry University of Allahabad Allahabad Uttar Pradesh India

Giuseppe Paolisso Department of Internal Medi-cine Surgical Neurological Metabolic Dis-ease and Geriatric Medicine Second University of Naples Naples Italy

Helios Pareja‐Galeano Department of Physiology School of Medicine University of Valencia Valencia Spain Fundacioacuten del Hospital Cliacutenico Universitario Valencia (FIHCUV‐ INCLIVA) Valencia Spain

Syed Ibrahim Rizvi Department of Biochemistry University of Allahabad Allahabad Uttar Pradesh India

Sy Saeed Department of Psychiatry and Behavioral Medicine Brody School of Medicine at East Carolina University Greenville NC USA

Fabiaacuten Sanchis‐Gomar Department of Physiology School of Medicine University of Valencia Valencia Spain Fundacioacuten del Hospital Cliacutenico Universitario Valencia (FIHCUV‐INCLIVA) Valencia Spain

Estela Santos‐Alves Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

S Manjunatha Endocrine Research Unit Mayo Clinic College of Medicine Rochester MN USA

Maria Fiatarone Singh Exercise Health and Performance Faculty Research Group Sydney Medical School The University of Sydney Lid-combe New South Wales Australia Hebrew SeniorLife Boston MA USA Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University Boston MA USA

Patsri Srisuwan Outpatient and Family Medicine Department Phramongkutklao Hospital and College of Medicine Bangkok Thailand

Richard J Stevenson Department of Psychology Macquarie University Sydney New South Wales Australia

Mark R Zielinski Department of Psychiatry Harvard Medical School and Veterans Affairs Boston Healthcare System West Roxbury MA USA

FoREWoRD

the brain is a plastic organ that is continuously changing and adapting to its environment because of this natural capacity for plasticity there has been an increasing interest from both scientific and public policy groups to attempt to leverage brain plasticity to prevent or treat neurological and psy-chiatric conditions From this perspective there have emerged three categories of treatments that attempt to take advantage of brain plasticity First there are traditional pharmaceutical treatments that try to manipulate the molecular milieu of the brain through medication thereby influencing the prevalence and trajectory of brain disorders unfortunately effective pharmaceutical treatments with minimal side effects and high compliance rates have remained elusive for many disorders of the brain thus in contrast to pharmaceutical approaches the other two approaches are nonphar-maceutical in nature and include (1) behavioral therapies (eg cognitive behavioral therapy) and (2) lifestyle changes (eg exercise habits) these two approaches are often referred to as ldquononpharmaceuti-calrdquo in the sense that they are not medication based However the term ldquononpharmaceuticalrdquo should not be confused with ldquononpharmacologicalrdquo indeed behavioral and lifestyle treatments are methods of manipulating the endogenous pharmacology of the brain

over the past decade there has been an explosion of scientific interest in ldquononpharmaceuticalrdquo approaches to brain plasticity especially those

approaches that include lifestyles (eg exercise habits) this body of work emerges within the context of a well‐established research demonstrating the impact of health behaviors on the function and integrity of visceral organs and physical health Amazingly it has been only relatively recently that the brain and its functions (eg cognition) have been considered as being closely linked to health behaviors such as physical activity and dietary habits indeed as the chapters in this book discuss the brain and its functions are highly susceptible to the same types of decay and dysfunction from engagement in unhealthy lifestyles as the rest of the body Fortunately massive amounts of research have now clearly demonstrated the importance of dietary and exercise habits with cognitive and brain function or diseases and suggest that these effects of unhealthy behaviors on the brain are modifiable For example the work by our group found that engagement in moderate‐intensity exercise several days a week for 1 year was sufficient for increasing the size of the hippocampus in a sample of cognitively healthy but sedentary elderly [1] interestingly the change in hippocampal volume was correlated with changes in spatial memory performance for the exercise group and not for the control group indicating that the changes in hippocampal volume were not a mean-ingless by‐product of greater exercise participation but rather that they had significant implications for cognitive function such findings indicate not only that the brain remains plastic but also that

xvi Foreword

engagement in exercise has the capability of modi-fying the structural integrity of the brain Many other studies have also reported similar effects of exercise physical activity and fitness on biomarkers brain health and cognitive function

As will be described throughout this book despite some consensus on the importance of exercise and dietary lifestyles for brain function there remains debate about the mechanisms the dosendashresponse and the extent to which these life-style choices are effective for both primary and secondary prevention of disease and long‐term treatment for the attenuation of cognitive or brain losses it will be necessary for well‐controlled randomized trials and longitudinal studies with larger sample sizes to more conclusively link these lifestyle approaches to improvements in cognitive and brain health Yet despite this need there is a growing consensus that dietary and exercise habits are important modifiable behaviors that directly influence cognitive and brain health throughout the lifespan the focus of this book titled Diet and

Exercise in Cognitive Function and Neurological Diseases addresses these topics and presents a timely and comprehensive review from world experts in neuroscience epidemiology neurology cognitive psychology nutrition genetics and exercise science this book will provide an excel-lent resource for students and researchers and serve as a guide for the development of future research projects and for the integration of health behaviors into clinical practice and public policies that strive to enhance cognitive and brain health

REFERENCE

1 erickson Ki et al exercise training increases size of hippocampus and improves memory Proc Natl Acad Sci U S A 2011 108(7) pp 3017ndash22

Kirk i erickson

Department of Psychology University of Pittsburgh

Pittsburgh PA USA

this is my warm welcome to the world of ldquodiet and exercise in cognitive function and neurological diseasesrdquo eating food and exercise are two fundamental activities in animal species they use three macronutrients for energy including carbohy-drates proteins and fatty acids Although the world Health organization (wHo) prioritizes ldquostopping hungerrdquo as a highest priority overnu-trition clearly is a concern on numerous health problems in the united states our body does not have positive mechanisms to remove overnu-trition which is why exercise has been a major intervention in order to reduce energy that is taken too much

the central nervous system (Cns) is a hungry tissue for energy it needs energy for a wide variety of functions and therefore when metabolic path-ways are altered Cns is in a big trouble in diabetes high glucose in the blood is characteristic due to deficits in insulin or insulin pathways the Alzheimerrsquos disease (Ad) which is a major cause of dementia shares characteristics of diabetes in the brainmdashit has been proposed to be classified as ldquotype 3 diabetesrdquo in Ad some neurons cannot take glucose inside as well as cannot use the secondary energy source neither with abundant glucose the body thinks why we should use the second energy source ketone bodies (and it does not use ketone

bodies) to turn the situation better glucose levels should be lower so that the neurons start to use ketone bodies

in Ad and some neurological diseases reducing glucose seems to be an effective strategy to provide the secondary energy to the neurons Low‐carbohydrate (low‐carb) diet has a direct effect on reducing glucose and importantly reducing insulin we now know reducing iGF‐1insulin signal can extend lifespan in a wide variety of species from worms to flies and to mammals Low‐carb diet may have a beneficial effect on extending lifespan

Ketogenic diet uses low carb to reduce glucose and high lipids to provide ketone bodies which is a promising treatment in the future Ketogenic diet has originally been used for the treatment of a neurological disease epilepsy However it needs a caution about complex effects of lipids some of which have negative effects on patients with cardiovascular diseases it is essential to shift the diet strategy to the lipids that have neutral or beneficial effects on the health Applications of the diet to diabetes and Ad have been considered

this book will provide a nicely blended over-view of diet and exercise it has chapters describing various types of diet including among

FoREWoRD

xviii Foreword

others ketogenic diet Mediterranean diet and n‐3 (omega‐3) diet other chapters describe a wide variety of benefits on exercise some toxic nutritional metabolites are also getting attention including homocysteine which is linked to methi-onine metabolism Methionine together with folic acidvitamin b12 has been implicated to play a role in normal aging

i would like to thank the editors for the opportunity to write Foreword of this exciting book

shin Murakami Phd

Department of Basic Sciences College of Osteopathic Medicine

Touro University California Vallejo CA USA

Diet and exercise play an important role in maintaining good cognitive function and longevity Macro‐ and micronutrients not only provide energy and building material to the body but also have ability to prevent and protect against age‐related neurological disor-ders Exercise initiates the maintenance of good cardiorespiratory cardiovascular cerebrovascular and muscular fitness by increasing energy con-sumption improving insulin sensitivity increasing blood flow increasing the expression of brain‐derived neurotrophic factor and reducing inflammation Western diet which is enriched in refined carbohy-drates (simple sugars) partially hydrogenated oils (peanut corn soybean and canola) and proteins of animal origin (enriched in corn‐based livestock) is high in salt and low in fiber At present in Western diet the ratio of arachidonic acid (ARA) to docosa-hexaenoic acid (DHA) is about 201 By contrast the Paleolithic diet (stone‐age diet) on which our forefathers lived and survived throughout their his-tory contained high amounts of fresh fruits green vegetables lean meats fish seeds piths and barks with ARA to DHA ratio of 11 Long‐term con-sumption of Western diet produces detrimental effect on health not only by inducing an increase in systemic and brain inflammation and oxidative stress through the stimulation of insulin‐like growth factor 1 (IGF‐1) and Toll‐like receptors and generation of high levels of ARA‐derived lipid mediators but also by mediating abnormalities in mitochondrial function along with the induction of

insulin resistance and leptin resistance in visceral organs and the brain The onset and induction of oxidative stress neuroinflammation and abnormal-ities in mitochondrial function are closely associated with impairments in frontal limbic and hippocampal systems leading to changes in learning memory cognition and hedonics In visceral tissues oxidative stress and inflammation along with genetic and environmental factors promote obesity diabetes metabolic syndrome heart disease and cancer These pathological conditions are risk factors for neurological disorders (stroke AD and depression) Thus incidences of neurological disorders are two‐ to threefold higher in patients with type 2 diabetes metabolic syndrome and cardiovascular diseases compared to normal subjects of the same age

The Mediterranean diet which is enriched in fruits vegetables garlic legumes and unrefined cereals and has moderate amount of fish and high amount of olive oil along with modest intake of red wine produces anti‐inflammatory antioxidant and antidiabetic effects leading to cardio‐ and neuroprotection in heart disease and neurological disorders

Exercise initiates the maintenance of good car-diorespiratory cardiovascular cerebrovascular and muscular fitness by preventing metabolic imbalance increasing energy consumption improving insulin sensitivity increasing blood flow elevating levels of brain‐derived neurotrophic factor reducing inflammation and enhancing learning and memory

PREFACE

xx PREFACE

Good nutrition daily exercise and adequate sleep are the foundations for maintaining optimal health

Information on diet and exercise is scattered throughout the literature in the form of original papers reviews and some books These books describe the effects of diet and exercise on visceral organs The purpose of this edited book is to pro-vide readers with a comprehensive and cutting‐edge information on the effects of diet and exercise on cognitive function and age‐related visceral and brain diseases in a manner which is useful not only to students and teachers but also to researchers dietitians nutritionists exercise physiologists and physicians To the best of our knowledge this edited book will be the first to provide a comprehensive description of signal transduction processes associated with the effects of diet and exercise on the cognitive function

This edited book has 28 chapters Chapters 1ndash9 describe the effects of various diet patterns on metabolic changes in visceral organs and the brain Chapters 10ndash26 provide information on the effects of diet and exercise on cognitive function and age‐related neurological disorders Chapter 27 deals

with the role of salt in the pathogenesis of dementia and stroke Finally Chapter 28 deals with perspective on the current progress that will be important for future studies on the effects of diet and exercise on cognitive function in normal subjects and age‐related neurological disorders

Our contributors have tried to ensure uniformity and mode of presentation simple and we have made sure that the progression of subject matter from one topic to another is logical Each chapter provides an extensive bibliography for readers to consult For the sake of simplicity and uniformity a large number of figures with chemical structures of metabolites along with line diagrams of colored signal transduction pathways are included We hope that our attempt to integrate and consolidate the knowledge on the effects of diet and exercise on cognitive function will initiate more studies on molecular mechanisms that link among diet and exercise with cognitive function in normal subjects and patients with age‐related neu-rological disorders

Tahira Farooqui Akhlaq A Farooqui

We thank all the authors of this book who shared their expertise by contributing chapters of a high standard thus making our editorial task much easier We are grateful to Justin Jeffryes Editorial Director at Wiley‐Blackwell for his cooperation and patience during this process We are also

thankful to Stephanie Dollan Senior Editorial Assistant at Wiley‐Blackwell for her professional handling of the manuscript

Tahira FarooquiAkhlaq A Farooqui

ACKNOWLEDGMENTS

Diet and Exercise in Cognitive Function and Neurological Diseases First Edition Edited by Tahira Farooqui and Akhlaq A Farooqui copy 2015 John Wiley amp Sons Inc Published 2015 by John Wiley amp Sons Inc

11 INTRODUCTION

Nutritionndashgene interactions play a pivotal role in cognitive function and neurological disease throughout life Nutrition is one of many environ-mental factors that profoundly alter the phenotypic expression of a given genotype with major impli-cations for development metabolism health and disease [1ndash4] These effects are mediated by changes in expression of multiple genes and can involve epigenetic mechanisms nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence Responses to nutrition are in turn affected by individual genetic variability The effects of nutrition on gene expression are exerted throughout the life cycle with prenatal and early postnatal life being especially critical periods for optimal development Changes in gene expression may be dynamic and short term stable and long term and even heritable between cell divisions and across generations

This review focuses on the following key topics First a short overview is provided on the role of nutrition in cognitive neuroscience Second mecha-nisms underlying nutritionndashgene interactions are discussed especially in relation to the roles of epige-netics and genetic variability in neuroscience

Third attention is focused on the importance of environment and epigenetics in neurological health and disease Finally the role of early nutrition in brain development and later neurological disease is addressed Overall this review highlights the criti-cal importance of nutritionndashgene interactions to optimal neurological function and prevention and treatment of multiple neurological disorders

12 NUTRITION AND COGNITIVE NEUROSCIENCE

The role of nutrition in cognitive neuroscience is highly complex because as with all aspects of nutrition it is multifactorial It is not concerned simply with the impact of a single chemical on the brain but with numerous interactions between multiple nutrients metabolites food and other environmental and genetic factors Nevertheless considerable evidence now links many aspects of nutrition with cognition mental health and well‐being neurological dysfunction and disease [1ndash9] Protective roles are suggested for the Mediterranean diet optimal energy status fish fruits vegetables polyphenols omega‐3 polyunsaturated fatty acids iron zinc copper and numerous vitamins

NUTRITION GENES AND NEUROSCIENCE IMPLICATIONS FOR DEVELOPMENT HEALTH AND DISEASE

Margaret Joy DaunceyWolfson College University of Cambridge Cambridge UK

1

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

Contributors xi

Foreword Kirk I Erickson xv

Foreword Shin Murakami xvii

Preface Tahira Farooqui and Akhlaq A Farooqui xix

Acknowledgments xxi

1 Nutrition Genes and Neuroscience Implications for Development Health and Disease 1Margaret Joy Dauncey

2 Neurochemical Effects of Western Diet Consumption on Human Brain 15Akhlaq A Farooqui and Tahira Farooqui

3 Effect of Mediterranean Diet on Human Health in Seniors Relationship with Telomers 29Virginia Boccardi and Giuseppe Paolisso

4 Effect of a Mediterranean Diet on Mental and Physical Quality of Life 39Marialaura Bonaccio Giovanni de Gaetano and Licia Iacoviello

5 Ketogenic Diets for the Treatment of Neurologic Disease 47Christa W Habela and Eric H Kossoff

6 Levels of n‐3 Fatty Acids and their Metabolites in the Brain Their Impact on Brain Function and Neurological Disorders 59Akhlaq A Farooqui and Tahira Farooqui

7 Homocysteine Levels in Neurological Disorders 73Ahmed A Moustafa Doaa H Hewedi Abeer M Eissa Dorota Frydecka and Błazej Misiak

8 Table Salt and Dementia 83Surender R Neravetla and Shantanu R Neravetla

CoNTENTS

viii Contents

9 Contribution of Diet and Exercise in the Pathogenesis of Major Depression 93Adrian L Lopresti

10 Role of Diet and Exercise in Diabetic Retinopathy 105Mohammad Shamsul Ola Haseeb A Khan and Abdullah S Alhomida

11 The Effect of Western Diet on Cognition in Humans 111Heather M Francis and Richard J Stevenson

12 Role of Diet and Exercise in Intervention of Age‐Induced Impairments 123Kanti Bhooshan Pandey and Syed Ibrahim Rizvi

13 Hormesis and Cognitive Function An EvolutionaryAdaptive Arabesque Leading to Longevity 133Alistair VW Nunn Geoffrey W Guy and Jimmy D Bell

14 Polyphenols and Cognitive Function 143Edwin D Lephart

15 Prevention of Dementia Through Modifiable Risk Factors 163Patsri Srisuwan

16 Physical Exercise Improves Cognition in Brain Disorders Alzheimerrsquos Disease 175Trevor Archer and Danilo Garcia

17 Molecular Biochemical and Physiological Basis of Beneficial Actions of Exercise 183Undurti N Das

18 Beneficial Effects of Exercise and Cognitive Training on Cognitive Functions in older Adults Introduction of Smart Aging Studies 205Rui Nouchi and Ryuta Kawashima

19 Exercise and Cognitive Functions 213Bijli Nanda and S Manjunatha

20 Role of Sleep in Cognition Immunity and Disease and Its Interaction with Exercise 225Mark R Zielinski and Dmitry Gerashchenko

21 Effect of Forced and Voluntary Exercise on Neural Plasticity Mediated by Astrocytes 241Caren Bernardi Mario Roberto Generosi Brauner and Carlos Alberto Gonccedilalves

22 Effect of Exercise on the Aging Brain 253Bonita L Marks

23 The Effects of Exercise on Neuronal Survival 267Michael J Chen

24 Exercise and Cognitive Function in older Adults 279Nicola J Gates and Maria Fiatarone Singh

25 Research Issues and Clinical Implications of Exercise Effects in the Treatment of Depressive and Anxiety Disorders 295A Garrett Hazelton Richard Bloch and Sy Saeed

Contents ix

26 Exercise‐Induced Protection Against Aging and Neurodegenerative Diseases Role of Redox‐ and Mitochondrial‐Based Alterations 309Inecircs Marques‐Aleixo Estela Santos‐Alves Paula I Moreira Paulo J Oliveira Joseacute Magalhatildees and Antoacutenio Ascensatildeo

27 Exercise Neuroplasticity and Growth Factors in Adolescence 323Helios Pareja‐Galeano Sara Mayero and Fabiaacuten Sanchis‐Gomar

28 Summary Perspective and Direction for Future Studies 339Tahira Farooqui and Akhlaq A Farooqui

Index 349

Abdullah S Alhomida Department of Biochem-istry College of Science King Saud University Riyadh Saudi Arabia

Trevor Archer Department of Psychology University of Gothenburg Gothenburg Sweden Network for Empowerment and Well‐Being Gothenburg Sweden

Antoacutenio Ascensatildeo Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Jimmy D Bell Department of Life Sciences Clipstone Building University of Westminster London UK

Caren Bernardi Programa de Poacutes-Graduaccedilatildeo Ciecircncias da Reabilitaccedilatildeo Universidade Federal de Ciecircncias da Sauacutede de Porto Alegre Porto Alegre Brazil

Richard Bloch Department of Psychiatry and Behavioral Medicine Brody School of Medicine at East Carolina University Greenville NC USA

Virginia Boccardi Department of Internal Medicine Surgical Neurological Metabolic Disease and Geriatric Medicine Second University of Naples Naples Italy

Marialaura Bonaccio Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Mario Roberto Generosi Brauner Escola de Educaccedilatildeo Fiacutesica (ESEF) Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Michael J Chen Department of Biological Sciences California State University Los Angeles CA USA

Undurti N Das UND Life Sciences Federal Way WA USA

Margaret Joy Dauncey Wolfson College University of Cambridge Cambridge UK

Abeer M Eissa Psychogeriatric Research Center Department of Psychiatry School of Medicine Ain Shams University Cairo Egypt

Kirk I Erickson Department of Psychology University of Pittsburgh Pittsburgh PA USA

Akhlaq A Farooqui Department of Molecular and Cellular Biochemistry College of Medicine The Ohio State University Columbus OH USA

Tahira Farooqui Department of Molecular and Cellular Biochemistry College of Medicine The Ohio State University Columbus OH USA

CoNTRIBUToRS

xii Contributors

Heather M Francis School of Psychology Science Department University of New South Wales Sydney New South Wales Australia

Dorota Frydecka Department and Clinic of Psychiatry Wrocław Medical University Wrocław Poland

Giovanni de Gaetano Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Danilo Garcia Network for Empowerment and Well‐Being Gothenburg Sweden Center for Ethics Law and Mental Health University of Gothenburg Gothenburg Sweden

Nicola J Gates School of Psychiatry Centre for Healthy Brain Ageing (CheBA) University of New South Wales Sydney New South Wales Australia Brain and Mind Psychology Sydney New South Wales Australia

Dmitry Gerashchenko Department of Psychiatry Harvard Medical School and Veterans Affairs Boston Healthcare System West Roxbury MA USA

Carlos Alberto Gonccedilalves Programa de Poacutes- Graduaccedilatildeo Ciecircncias da Reabilitaccedilatildeo Universi-dade Federal de Ciecircncias da Sauacutede de Porto Alegre Porto Alegre Brazil Departamento de Bioquiacutemica Instituto de Ciecircncias Baacutesicas da Sauacutede Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Geoffrey W Guy GW Pharmaceuticals Porton Down Salisbury Wiltshire UK

Christa W Habela Division of Child Neurology Department of Neurology The Johns Hopkins School of Medicine Baltimore MD USA

A Garrett Hazelton Department of Psychiatry and Behavioral Medicine Brody School of Med-icine at East Carolina University Greenville NC USA

Doaa H Hewedi Psychogeriatric Research Center Department of Psychiatry School of Medicine Ain Shams University Cairo Egypt

Licia Iacoviello Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Ryuta Kawashima Smart Ageing International Research Centre Institute of Development Aging and Cancer Tohoku University Sendai Japan

Haseeb A Khan Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia

Eric H Kossoff Division of Child Neurology Department of Neurology The Johns Hopkins School of Medicine Baltimore MD USA

Edwin D Lephart Department of Physiology and Developmental Biology and The Neuroscience Center College of Life Sciences Brigham Young University Provo UT USA

Adrian l Lopresti School of Psychology and Exercise Science Murdoch University Murdoch Western Australia Australia

Joseacute Magalhatildees Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Inecircs Marques‐Aleixo Research Center in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Bonita L Marks Departments of Exercise and Sport Science Emergency Medicine and Allied Health Sciences University of North Carolina at Chapel Hill Chapel Hill NC USA

Sara Mayero Department of Psychiatry Hospital Moncloa Madrid Spain

Błazej Misiak Department and Clinic of Psychiatry Wrocław Medical University Wrocław Poland Department of Genetics Wrocław Medical University Wrocław Poland

Paula I Moreira Centre for Neuroscience and Cell Biology (CNC) UC‐BiotechBiocant Park University of Coimbra Cantanhede Portugal Institute of Physiology Faculty of Medicine University of Coimbra Coimbra Portugal

Ahmed A Moustafa School of Social Sciences and Psychology amp Marcs Institute for Brain and Behaviour University of Western Sydney Sydney New South Wales Australia

Shin Murakami Department of Basic Sciences College of Osteopathic Medicine Touro Univer-sity‐California Mare Island Vallejo CA USA

Bijli Nanda Department of Physiology School of Medical Sciences and Research Sharda University Greater Noida Uttar Pradesh India

Shantanu R Neravetla Medical Director Heart Health Now LLC Springfield OH USA

Contributors xiii

Surender R Neravetla Director Cardiac Surgery Springfield Regional Medical Center Spring-field OH USA Wright State University Dayton OH USA

Rui Nouchi Human and Social Response Research Division International Research Institute of Disaster Science Tohoku University Sendai Japan Smart Ageing International Research Centre Institute of Development Aging and Cancer Tohoku University Sendai Japan

Alistair VW Nunn School of Pharmacy Uni-versity of Reading Reading UK

Mohammad Shamsul ola Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia

Paulo J oliveira Centre for Neuroscience and Cell Biology (CNC) UC‐BiotechBiocant Park University of Coimbra Cantanhede Portugal

Kanti Bhooshan Pandey Department of Biochemistry University of Allahabad Allahabad Uttar Pradesh India

Giuseppe Paolisso Department of Internal Medi-cine Surgical Neurological Metabolic Dis-ease and Geriatric Medicine Second University of Naples Naples Italy

Helios Pareja‐Galeano Department of Physiology School of Medicine University of Valencia Valencia Spain Fundacioacuten del Hospital Cliacutenico Universitario Valencia (FIHCUV‐ INCLIVA) Valencia Spain

Syed Ibrahim Rizvi Department of Biochemistry University of Allahabad Allahabad Uttar Pradesh India

Sy Saeed Department of Psychiatry and Behavioral Medicine Brody School of Medicine at East Carolina University Greenville NC USA

Fabiaacuten Sanchis‐Gomar Department of Physiology School of Medicine University of Valencia Valencia Spain Fundacioacuten del Hospital Cliacutenico Universitario Valencia (FIHCUV‐INCLIVA) Valencia Spain

Estela Santos‐Alves Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

S Manjunatha Endocrine Research Unit Mayo Clinic College of Medicine Rochester MN USA

Maria Fiatarone Singh Exercise Health and Performance Faculty Research Group Sydney Medical School The University of Sydney Lid-combe New South Wales Australia Hebrew SeniorLife Boston MA USA Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University Boston MA USA

Patsri Srisuwan Outpatient and Family Medicine Department Phramongkutklao Hospital and College of Medicine Bangkok Thailand

Richard J Stevenson Department of Psychology Macquarie University Sydney New South Wales Australia

Mark R Zielinski Department of Psychiatry Harvard Medical School and Veterans Affairs Boston Healthcare System West Roxbury MA USA

FoREWoRD

the brain is a plastic organ that is continuously changing and adapting to its environment because of this natural capacity for plasticity there has been an increasing interest from both scientific and public policy groups to attempt to leverage brain plasticity to prevent or treat neurological and psy-chiatric conditions From this perspective there have emerged three categories of treatments that attempt to take advantage of brain plasticity First there are traditional pharmaceutical treatments that try to manipulate the molecular milieu of the brain through medication thereby influencing the prevalence and trajectory of brain disorders unfortunately effective pharmaceutical treatments with minimal side effects and high compliance rates have remained elusive for many disorders of the brain thus in contrast to pharmaceutical approaches the other two approaches are nonphar-maceutical in nature and include (1) behavioral therapies (eg cognitive behavioral therapy) and (2) lifestyle changes (eg exercise habits) these two approaches are often referred to as ldquononpharmaceuti-calrdquo in the sense that they are not medication based However the term ldquononpharmaceuticalrdquo should not be confused with ldquononpharmacologicalrdquo indeed behavioral and lifestyle treatments are methods of manipulating the endogenous pharmacology of the brain

over the past decade there has been an explosion of scientific interest in ldquononpharmaceuticalrdquo approaches to brain plasticity especially those

approaches that include lifestyles (eg exercise habits) this body of work emerges within the context of a well‐established research demonstrating the impact of health behaviors on the function and integrity of visceral organs and physical health Amazingly it has been only relatively recently that the brain and its functions (eg cognition) have been considered as being closely linked to health behaviors such as physical activity and dietary habits indeed as the chapters in this book discuss the brain and its functions are highly susceptible to the same types of decay and dysfunction from engagement in unhealthy lifestyles as the rest of the body Fortunately massive amounts of research have now clearly demonstrated the importance of dietary and exercise habits with cognitive and brain function or diseases and suggest that these effects of unhealthy behaviors on the brain are modifiable For example the work by our group found that engagement in moderate‐intensity exercise several days a week for 1 year was sufficient for increasing the size of the hippocampus in a sample of cognitively healthy but sedentary elderly [1] interestingly the change in hippocampal volume was correlated with changes in spatial memory performance for the exercise group and not for the control group indicating that the changes in hippocampal volume were not a mean-ingless by‐product of greater exercise participation but rather that they had significant implications for cognitive function such findings indicate not only that the brain remains plastic but also that

xvi Foreword

engagement in exercise has the capability of modi-fying the structural integrity of the brain Many other studies have also reported similar effects of exercise physical activity and fitness on biomarkers brain health and cognitive function

As will be described throughout this book despite some consensus on the importance of exercise and dietary lifestyles for brain function there remains debate about the mechanisms the dosendashresponse and the extent to which these life-style choices are effective for both primary and secondary prevention of disease and long‐term treatment for the attenuation of cognitive or brain losses it will be necessary for well‐controlled randomized trials and longitudinal studies with larger sample sizes to more conclusively link these lifestyle approaches to improvements in cognitive and brain health Yet despite this need there is a growing consensus that dietary and exercise habits are important modifiable behaviors that directly influence cognitive and brain health throughout the lifespan the focus of this book titled Diet and

Exercise in Cognitive Function and Neurological Diseases addresses these topics and presents a timely and comprehensive review from world experts in neuroscience epidemiology neurology cognitive psychology nutrition genetics and exercise science this book will provide an excel-lent resource for students and researchers and serve as a guide for the development of future research projects and for the integration of health behaviors into clinical practice and public policies that strive to enhance cognitive and brain health

REFERENCE

1 erickson Ki et al exercise training increases size of hippocampus and improves memory Proc Natl Acad Sci U S A 2011 108(7) pp 3017ndash22

Kirk i erickson

Department of Psychology University of Pittsburgh

Pittsburgh PA USA

this is my warm welcome to the world of ldquodiet and exercise in cognitive function and neurological diseasesrdquo eating food and exercise are two fundamental activities in animal species they use three macronutrients for energy including carbohy-drates proteins and fatty acids Although the world Health organization (wHo) prioritizes ldquostopping hungerrdquo as a highest priority overnu-trition clearly is a concern on numerous health problems in the united states our body does not have positive mechanisms to remove overnu-trition which is why exercise has been a major intervention in order to reduce energy that is taken too much

the central nervous system (Cns) is a hungry tissue for energy it needs energy for a wide variety of functions and therefore when metabolic path-ways are altered Cns is in a big trouble in diabetes high glucose in the blood is characteristic due to deficits in insulin or insulin pathways the Alzheimerrsquos disease (Ad) which is a major cause of dementia shares characteristics of diabetes in the brainmdashit has been proposed to be classified as ldquotype 3 diabetesrdquo in Ad some neurons cannot take glucose inside as well as cannot use the secondary energy source neither with abundant glucose the body thinks why we should use the second energy source ketone bodies (and it does not use ketone

bodies) to turn the situation better glucose levels should be lower so that the neurons start to use ketone bodies

in Ad and some neurological diseases reducing glucose seems to be an effective strategy to provide the secondary energy to the neurons Low‐carbohydrate (low‐carb) diet has a direct effect on reducing glucose and importantly reducing insulin we now know reducing iGF‐1insulin signal can extend lifespan in a wide variety of species from worms to flies and to mammals Low‐carb diet may have a beneficial effect on extending lifespan

Ketogenic diet uses low carb to reduce glucose and high lipids to provide ketone bodies which is a promising treatment in the future Ketogenic diet has originally been used for the treatment of a neurological disease epilepsy However it needs a caution about complex effects of lipids some of which have negative effects on patients with cardiovascular diseases it is essential to shift the diet strategy to the lipids that have neutral or beneficial effects on the health Applications of the diet to diabetes and Ad have been considered

this book will provide a nicely blended over-view of diet and exercise it has chapters describing various types of diet including among

FoREWoRD

xviii Foreword

others ketogenic diet Mediterranean diet and n‐3 (omega‐3) diet other chapters describe a wide variety of benefits on exercise some toxic nutritional metabolites are also getting attention including homocysteine which is linked to methi-onine metabolism Methionine together with folic acidvitamin b12 has been implicated to play a role in normal aging

i would like to thank the editors for the opportunity to write Foreword of this exciting book

shin Murakami Phd

Department of Basic Sciences College of Osteopathic Medicine

Touro University California Vallejo CA USA

Diet and exercise play an important role in maintaining good cognitive function and longevity Macro‐ and micronutrients not only provide energy and building material to the body but also have ability to prevent and protect against age‐related neurological disor-ders Exercise initiates the maintenance of good cardiorespiratory cardiovascular cerebrovascular and muscular fitness by increasing energy con-sumption improving insulin sensitivity increasing blood flow increasing the expression of brain‐derived neurotrophic factor and reducing inflammation Western diet which is enriched in refined carbohy-drates (simple sugars) partially hydrogenated oils (peanut corn soybean and canola) and proteins of animal origin (enriched in corn‐based livestock) is high in salt and low in fiber At present in Western diet the ratio of arachidonic acid (ARA) to docosa-hexaenoic acid (DHA) is about 201 By contrast the Paleolithic diet (stone‐age diet) on which our forefathers lived and survived throughout their his-tory contained high amounts of fresh fruits green vegetables lean meats fish seeds piths and barks with ARA to DHA ratio of 11 Long‐term con-sumption of Western diet produces detrimental effect on health not only by inducing an increase in systemic and brain inflammation and oxidative stress through the stimulation of insulin‐like growth factor 1 (IGF‐1) and Toll‐like receptors and generation of high levels of ARA‐derived lipid mediators but also by mediating abnormalities in mitochondrial function along with the induction of

insulin resistance and leptin resistance in visceral organs and the brain The onset and induction of oxidative stress neuroinflammation and abnormal-ities in mitochondrial function are closely associated with impairments in frontal limbic and hippocampal systems leading to changes in learning memory cognition and hedonics In visceral tissues oxidative stress and inflammation along with genetic and environmental factors promote obesity diabetes metabolic syndrome heart disease and cancer These pathological conditions are risk factors for neurological disorders (stroke AD and depression) Thus incidences of neurological disorders are two‐ to threefold higher in patients with type 2 diabetes metabolic syndrome and cardiovascular diseases compared to normal subjects of the same age

The Mediterranean diet which is enriched in fruits vegetables garlic legumes and unrefined cereals and has moderate amount of fish and high amount of olive oil along with modest intake of red wine produces anti‐inflammatory antioxidant and antidiabetic effects leading to cardio‐ and neuroprotection in heart disease and neurological disorders

Exercise initiates the maintenance of good car-diorespiratory cardiovascular cerebrovascular and muscular fitness by preventing metabolic imbalance increasing energy consumption improving insulin sensitivity increasing blood flow elevating levels of brain‐derived neurotrophic factor reducing inflammation and enhancing learning and memory

PREFACE

xx PREFACE

Good nutrition daily exercise and adequate sleep are the foundations for maintaining optimal health

Information on diet and exercise is scattered throughout the literature in the form of original papers reviews and some books These books describe the effects of diet and exercise on visceral organs The purpose of this edited book is to pro-vide readers with a comprehensive and cutting‐edge information on the effects of diet and exercise on cognitive function and age‐related visceral and brain diseases in a manner which is useful not only to students and teachers but also to researchers dietitians nutritionists exercise physiologists and physicians To the best of our knowledge this edited book will be the first to provide a comprehensive description of signal transduction processes associated with the effects of diet and exercise on the cognitive function

This edited book has 28 chapters Chapters 1ndash9 describe the effects of various diet patterns on metabolic changes in visceral organs and the brain Chapters 10ndash26 provide information on the effects of diet and exercise on cognitive function and age‐related neurological disorders Chapter 27 deals

with the role of salt in the pathogenesis of dementia and stroke Finally Chapter 28 deals with perspective on the current progress that will be important for future studies on the effects of diet and exercise on cognitive function in normal subjects and age‐related neurological disorders

Our contributors have tried to ensure uniformity and mode of presentation simple and we have made sure that the progression of subject matter from one topic to another is logical Each chapter provides an extensive bibliography for readers to consult For the sake of simplicity and uniformity a large number of figures with chemical structures of metabolites along with line diagrams of colored signal transduction pathways are included We hope that our attempt to integrate and consolidate the knowledge on the effects of diet and exercise on cognitive function will initiate more studies on molecular mechanisms that link among diet and exercise with cognitive function in normal subjects and patients with age‐related neu-rological disorders

Tahira Farooqui Akhlaq A Farooqui

We thank all the authors of this book who shared their expertise by contributing chapters of a high standard thus making our editorial task much easier We are grateful to Justin Jeffryes Editorial Director at Wiley‐Blackwell for his cooperation and patience during this process We are also

thankful to Stephanie Dollan Senior Editorial Assistant at Wiley‐Blackwell for her professional handling of the manuscript

Tahira FarooquiAkhlaq A Farooqui

ACKNOWLEDGMENTS

Diet and Exercise in Cognitive Function and Neurological Diseases First Edition Edited by Tahira Farooqui and Akhlaq A Farooqui copy 2015 John Wiley amp Sons Inc Published 2015 by John Wiley amp Sons Inc

11 INTRODUCTION

Nutritionndashgene interactions play a pivotal role in cognitive function and neurological disease throughout life Nutrition is one of many environ-mental factors that profoundly alter the phenotypic expression of a given genotype with major impli-cations for development metabolism health and disease [1ndash4] These effects are mediated by changes in expression of multiple genes and can involve epigenetic mechanisms nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence Responses to nutrition are in turn affected by individual genetic variability The effects of nutrition on gene expression are exerted throughout the life cycle with prenatal and early postnatal life being especially critical periods for optimal development Changes in gene expression may be dynamic and short term stable and long term and even heritable between cell divisions and across generations

This review focuses on the following key topics First a short overview is provided on the role of nutrition in cognitive neuroscience Second mecha-nisms underlying nutritionndashgene interactions are discussed especially in relation to the roles of epige-netics and genetic variability in neuroscience

Third attention is focused on the importance of environment and epigenetics in neurological health and disease Finally the role of early nutrition in brain development and later neurological disease is addressed Overall this review highlights the criti-cal importance of nutritionndashgene interactions to optimal neurological function and prevention and treatment of multiple neurological disorders

12 NUTRITION AND COGNITIVE NEUROSCIENCE

The role of nutrition in cognitive neuroscience is highly complex because as with all aspects of nutrition it is multifactorial It is not concerned simply with the impact of a single chemical on the brain but with numerous interactions between multiple nutrients metabolites food and other environmental and genetic factors Nevertheless considerable evidence now links many aspects of nutrition with cognition mental health and well‐being neurological dysfunction and disease [1ndash9] Protective roles are suggested for the Mediterranean diet optimal energy status fish fruits vegetables polyphenols omega‐3 polyunsaturated fatty acids iron zinc copper and numerous vitamins

NUTRITION GENES AND NEUROSCIENCE IMPLICATIONS FOR DEVELOPMENT HEALTH AND DISEASE

Margaret Joy DaunceyWolfson College University of Cambridge Cambridge UK

1

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

viii Contents

9 Contribution of Diet and Exercise in the Pathogenesis of Major Depression 93Adrian L Lopresti

10 Role of Diet and Exercise in Diabetic Retinopathy 105Mohammad Shamsul Ola Haseeb A Khan and Abdullah S Alhomida

11 The Effect of Western Diet on Cognition in Humans 111Heather M Francis and Richard J Stevenson

12 Role of Diet and Exercise in Intervention of Age‐Induced Impairments 123Kanti Bhooshan Pandey and Syed Ibrahim Rizvi

13 Hormesis and Cognitive Function An EvolutionaryAdaptive Arabesque Leading to Longevity 133Alistair VW Nunn Geoffrey W Guy and Jimmy D Bell

14 Polyphenols and Cognitive Function 143Edwin D Lephart

15 Prevention of Dementia Through Modifiable Risk Factors 163Patsri Srisuwan

16 Physical Exercise Improves Cognition in Brain Disorders Alzheimerrsquos Disease 175Trevor Archer and Danilo Garcia

17 Molecular Biochemical and Physiological Basis of Beneficial Actions of Exercise 183Undurti N Das

18 Beneficial Effects of Exercise and Cognitive Training on Cognitive Functions in older Adults Introduction of Smart Aging Studies 205Rui Nouchi and Ryuta Kawashima

19 Exercise and Cognitive Functions 213Bijli Nanda and S Manjunatha

20 Role of Sleep in Cognition Immunity and Disease and Its Interaction with Exercise 225Mark R Zielinski and Dmitry Gerashchenko

21 Effect of Forced and Voluntary Exercise on Neural Plasticity Mediated by Astrocytes 241Caren Bernardi Mario Roberto Generosi Brauner and Carlos Alberto Gonccedilalves

22 Effect of Exercise on the Aging Brain 253Bonita L Marks

23 The Effects of Exercise on Neuronal Survival 267Michael J Chen

24 Exercise and Cognitive Function in older Adults 279Nicola J Gates and Maria Fiatarone Singh

25 Research Issues and Clinical Implications of Exercise Effects in the Treatment of Depressive and Anxiety Disorders 295A Garrett Hazelton Richard Bloch and Sy Saeed

Contents ix

26 Exercise‐Induced Protection Against Aging and Neurodegenerative Diseases Role of Redox‐ and Mitochondrial‐Based Alterations 309Inecircs Marques‐Aleixo Estela Santos‐Alves Paula I Moreira Paulo J Oliveira Joseacute Magalhatildees and Antoacutenio Ascensatildeo

27 Exercise Neuroplasticity and Growth Factors in Adolescence 323Helios Pareja‐Galeano Sara Mayero and Fabiaacuten Sanchis‐Gomar

28 Summary Perspective and Direction for Future Studies 339Tahira Farooqui and Akhlaq A Farooqui

Index 349

Abdullah S Alhomida Department of Biochem-istry College of Science King Saud University Riyadh Saudi Arabia

Trevor Archer Department of Psychology University of Gothenburg Gothenburg Sweden Network for Empowerment and Well‐Being Gothenburg Sweden

Antoacutenio Ascensatildeo Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Jimmy D Bell Department of Life Sciences Clipstone Building University of Westminster London UK

Caren Bernardi Programa de Poacutes-Graduaccedilatildeo Ciecircncias da Reabilitaccedilatildeo Universidade Federal de Ciecircncias da Sauacutede de Porto Alegre Porto Alegre Brazil

Richard Bloch Department of Psychiatry and Behavioral Medicine Brody School of Medicine at East Carolina University Greenville NC USA

Virginia Boccardi Department of Internal Medicine Surgical Neurological Metabolic Disease and Geriatric Medicine Second University of Naples Naples Italy

Marialaura Bonaccio Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Mario Roberto Generosi Brauner Escola de Educaccedilatildeo Fiacutesica (ESEF) Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Michael J Chen Department of Biological Sciences California State University Los Angeles CA USA

Undurti N Das UND Life Sciences Federal Way WA USA

Margaret Joy Dauncey Wolfson College University of Cambridge Cambridge UK

Abeer M Eissa Psychogeriatric Research Center Department of Psychiatry School of Medicine Ain Shams University Cairo Egypt

Kirk I Erickson Department of Psychology University of Pittsburgh Pittsburgh PA USA

Akhlaq A Farooqui Department of Molecular and Cellular Biochemistry College of Medicine The Ohio State University Columbus OH USA

Tahira Farooqui Department of Molecular and Cellular Biochemistry College of Medicine The Ohio State University Columbus OH USA

CoNTRIBUToRS

xii Contributors

Heather M Francis School of Psychology Science Department University of New South Wales Sydney New South Wales Australia

Dorota Frydecka Department and Clinic of Psychiatry Wrocław Medical University Wrocław Poland

Giovanni de Gaetano Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Danilo Garcia Network for Empowerment and Well‐Being Gothenburg Sweden Center for Ethics Law and Mental Health University of Gothenburg Gothenburg Sweden

Nicola J Gates School of Psychiatry Centre for Healthy Brain Ageing (CheBA) University of New South Wales Sydney New South Wales Australia Brain and Mind Psychology Sydney New South Wales Australia

Dmitry Gerashchenko Department of Psychiatry Harvard Medical School and Veterans Affairs Boston Healthcare System West Roxbury MA USA

Carlos Alberto Gonccedilalves Programa de Poacutes- Graduaccedilatildeo Ciecircncias da Reabilitaccedilatildeo Universi-dade Federal de Ciecircncias da Sauacutede de Porto Alegre Porto Alegre Brazil Departamento de Bioquiacutemica Instituto de Ciecircncias Baacutesicas da Sauacutede Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Geoffrey W Guy GW Pharmaceuticals Porton Down Salisbury Wiltshire UK

Christa W Habela Division of Child Neurology Department of Neurology The Johns Hopkins School of Medicine Baltimore MD USA

A Garrett Hazelton Department of Psychiatry and Behavioral Medicine Brody School of Med-icine at East Carolina University Greenville NC USA

Doaa H Hewedi Psychogeriatric Research Center Department of Psychiatry School of Medicine Ain Shams University Cairo Egypt

Licia Iacoviello Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Ryuta Kawashima Smart Ageing International Research Centre Institute of Development Aging and Cancer Tohoku University Sendai Japan

Haseeb A Khan Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia

Eric H Kossoff Division of Child Neurology Department of Neurology The Johns Hopkins School of Medicine Baltimore MD USA

Edwin D Lephart Department of Physiology and Developmental Biology and The Neuroscience Center College of Life Sciences Brigham Young University Provo UT USA

Adrian l Lopresti School of Psychology and Exercise Science Murdoch University Murdoch Western Australia Australia

Joseacute Magalhatildees Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Inecircs Marques‐Aleixo Research Center in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Bonita L Marks Departments of Exercise and Sport Science Emergency Medicine and Allied Health Sciences University of North Carolina at Chapel Hill Chapel Hill NC USA

Sara Mayero Department of Psychiatry Hospital Moncloa Madrid Spain

Błazej Misiak Department and Clinic of Psychiatry Wrocław Medical University Wrocław Poland Department of Genetics Wrocław Medical University Wrocław Poland

Paula I Moreira Centre for Neuroscience and Cell Biology (CNC) UC‐BiotechBiocant Park University of Coimbra Cantanhede Portugal Institute of Physiology Faculty of Medicine University of Coimbra Coimbra Portugal

Ahmed A Moustafa School of Social Sciences and Psychology amp Marcs Institute for Brain and Behaviour University of Western Sydney Sydney New South Wales Australia

Shin Murakami Department of Basic Sciences College of Osteopathic Medicine Touro Univer-sity‐California Mare Island Vallejo CA USA

Bijli Nanda Department of Physiology School of Medical Sciences and Research Sharda University Greater Noida Uttar Pradesh India

Shantanu R Neravetla Medical Director Heart Health Now LLC Springfield OH USA

Contributors xiii

Surender R Neravetla Director Cardiac Surgery Springfield Regional Medical Center Spring-field OH USA Wright State University Dayton OH USA

Rui Nouchi Human and Social Response Research Division International Research Institute of Disaster Science Tohoku University Sendai Japan Smart Ageing International Research Centre Institute of Development Aging and Cancer Tohoku University Sendai Japan

Alistair VW Nunn School of Pharmacy Uni-versity of Reading Reading UK

Mohammad Shamsul ola Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia

Paulo J oliveira Centre for Neuroscience and Cell Biology (CNC) UC‐BiotechBiocant Park University of Coimbra Cantanhede Portugal

Kanti Bhooshan Pandey Department of Biochemistry University of Allahabad Allahabad Uttar Pradesh India

Giuseppe Paolisso Department of Internal Medi-cine Surgical Neurological Metabolic Dis-ease and Geriatric Medicine Second University of Naples Naples Italy

Helios Pareja‐Galeano Department of Physiology School of Medicine University of Valencia Valencia Spain Fundacioacuten del Hospital Cliacutenico Universitario Valencia (FIHCUV‐ INCLIVA) Valencia Spain

Syed Ibrahim Rizvi Department of Biochemistry University of Allahabad Allahabad Uttar Pradesh India

Sy Saeed Department of Psychiatry and Behavioral Medicine Brody School of Medicine at East Carolina University Greenville NC USA

Fabiaacuten Sanchis‐Gomar Department of Physiology School of Medicine University of Valencia Valencia Spain Fundacioacuten del Hospital Cliacutenico Universitario Valencia (FIHCUV‐INCLIVA) Valencia Spain

Estela Santos‐Alves Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

S Manjunatha Endocrine Research Unit Mayo Clinic College of Medicine Rochester MN USA

Maria Fiatarone Singh Exercise Health and Performance Faculty Research Group Sydney Medical School The University of Sydney Lid-combe New South Wales Australia Hebrew SeniorLife Boston MA USA Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University Boston MA USA

Patsri Srisuwan Outpatient and Family Medicine Department Phramongkutklao Hospital and College of Medicine Bangkok Thailand

Richard J Stevenson Department of Psychology Macquarie University Sydney New South Wales Australia

Mark R Zielinski Department of Psychiatry Harvard Medical School and Veterans Affairs Boston Healthcare System West Roxbury MA USA

FoREWoRD

the brain is a plastic organ that is continuously changing and adapting to its environment because of this natural capacity for plasticity there has been an increasing interest from both scientific and public policy groups to attempt to leverage brain plasticity to prevent or treat neurological and psy-chiatric conditions From this perspective there have emerged three categories of treatments that attempt to take advantage of brain plasticity First there are traditional pharmaceutical treatments that try to manipulate the molecular milieu of the brain through medication thereby influencing the prevalence and trajectory of brain disorders unfortunately effective pharmaceutical treatments with minimal side effects and high compliance rates have remained elusive for many disorders of the brain thus in contrast to pharmaceutical approaches the other two approaches are nonphar-maceutical in nature and include (1) behavioral therapies (eg cognitive behavioral therapy) and (2) lifestyle changes (eg exercise habits) these two approaches are often referred to as ldquononpharmaceuti-calrdquo in the sense that they are not medication based However the term ldquononpharmaceuticalrdquo should not be confused with ldquononpharmacologicalrdquo indeed behavioral and lifestyle treatments are methods of manipulating the endogenous pharmacology of the brain

over the past decade there has been an explosion of scientific interest in ldquononpharmaceuticalrdquo approaches to brain plasticity especially those

approaches that include lifestyles (eg exercise habits) this body of work emerges within the context of a well‐established research demonstrating the impact of health behaviors on the function and integrity of visceral organs and physical health Amazingly it has been only relatively recently that the brain and its functions (eg cognition) have been considered as being closely linked to health behaviors such as physical activity and dietary habits indeed as the chapters in this book discuss the brain and its functions are highly susceptible to the same types of decay and dysfunction from engagement in unhealthy lifestyles as the rest of the body Fortunately massive amounts of research have now clearly demonstrated the importance of dietary and exercise habits with cognitive and brain function or diseases and suggest that these effects of unhealthy behaviors on the brain are modifiable For example the work by our group found that engagement in moderate‐intensity exercise several days a week for 1 year was sufficient for increasing the size of the hippocampus in a sample of cognitively healthy but sedentary elderly [1] interestingly the change in hippocampal volume was correlated with changes in spatial memory performance for the exercise group and not for the control group indicating that the changes in hippocampal volume were not a mean-ingless by‐product of greater exercise participation but rather that they had significant implications for cognitive function such findings indicate not only that the brain remains plastic but also that

xvi Foreword

engagement in exercise has the capability of modi-fying the structural integrity of the brain Many other studies have also reported similar effects of exercise physical activity and fitness on biomarkers brain health and cognitive function

As will be described throughout this book despite some consensus on the importance of exercise and dietary lifestyles for brain function there remains debate about the mechanisms the dosendashresponse and the extent to which these life-style choices are effective for both primary and secondary prevention of disease and long‐term treatment for the attenuation of cognitive or brain losses it will be necessary for well‐controlled randomized trials and longitudinal studies with larger sample sizes to more conclusively link these lifestyle approaches to improvements in cognitive and brain health Yet despite this need there is a growing consensus that dietary and exercise habits are important modifiable behaviors that directly influence cognitive and brain health throughout the lifespan the focus of this book titled Diet and

Exercise in Cognitive Function and Neurological Diseases addresses these topics and presents a timely and comprehensive review from world experts in neuroscience epidemiology neurology cognitive psychology nutrition genetics and exercise science this book will provide an excel-lent resource for students and researchers and serve as a guide for the development of future research projects and for the integration of health behaviors into clinical practice and public policies that strive to enhance cognitive and brain health

REFERENCE

1 erickson Ki et al exercise training increases size of hippocampus and improves memory Proc Natl Acad Sci U S A 2011 108(7) pp 3017ndash22

Kirk i erickson

Department of Psychology University of Pittsburgh

Pittsburgh PA USA

this is my warm welcome to the world of ldquodiet and exercise in cognitive function and neurological diseasesrdquo eating food and exercise are two fundamental activities in animal species they use three macronutrients for energy including carbohy-drates proteins and fatty acids Although the world Health organization (wHo) prioritizes ldquostopping hungerrdquo as a highest priority overnu-trition clearly is a concern on numerous health problems in the united states our body does not have positive mechanisms to remove overnu-trition which is why exercise has been a major intervention in order to reduce energy that is taken too much

the central nervous system (Cns) is a hungry tissue for energy it needs energy for a wide variety of functions and therefore when metabolic path-ways are altered Cns is in a big trouble in diabetes high glucose in the blood is characteristic due to deficits in insulin or insulin pathways the Alzheimerrsquos disease (Ad) which is a major cause of dementia shares characteristics of diabetes in the brainmdashit has been proposed to be classified as ldquotype 3 diabetesrdquo in Ad some neurons cannot take glucose inside as well as cannot use the secondary energy source neither with abundant glucose the body thinks why we should use the second energy source ketone bodies (and it does not use ketone

bodies) to turn the situation better glucose levels should be lower so that the neurons start to use ketone bodies

in Ad and some neurological diseases reducing glucose seems to be an effective strategy to provide the secondary energy to the neurons Low‐carbohydrate (low‐carb) diet has a direct effect on reducing glucose and importantly reducing insulin we now know reducing iGF‐1insulin signal can extend lifespan in a wide variety of species from worms to flies and to mammals Low‐carb diet may have a beneficial effect on extending lifespan

Ketogenic diet uses low carb to reduce glucose and high lipids to provide ketone bodies which is a promising treatment in the future Ketogenic diet has originally been used for the treatment of a neurological disease epilepsy However it needs a caution about complex effects of lipids some of which have negative effects on patients with cardiovascular diseases it is essential to shift the diet strategy to the lipids that have neutral or beneficial effects on the health Applications of the diet to diabetes and Ad have been considered

this book will provide a nicely blended over-view of diet and exercise it has chapters describing various types of diet including among

FoREWoRD

xviii Foreword

others ketogenic diet Mediterranean diet and n‐3 (omega‐3) diet other chapters describe a wide variety of benefits on exercise some toxic nutritional metabolites are also getting attention including homocysteine which is linked to methi-onine metabolism Methionine together with folic acidvitamin b12 has been implicated to play a role in normal aging

i would like to thank the editors for the opportunity to write Foreword of this exciting book

shin Murakami Phd

Department of Basic Sciences College of Osteopathic Medicine

Touro University California Vallejo CA USA

Diet and exercise play an important role in maintaining good cognitive function and longevity Macro‐ and micronutrients not only provide energy and building material to the body but also have ability to prevent and protect against age‐related neurological disor-ders Exercise initiates the maintenance of good cardiorespiratory cardiovascular cerebrovascular and muscular fitness by increasing energy con-sumption improving insulin sensitivity increasing blood flow increasing the expression of brain‐derived neurotrophic factor and reducing inflammation Western diet which is enriched in refined carbohy-drates (simple sugars) partially hydrogenated oils (peanut corn soybean and canola) and proteins of animal origin (enriched in corn‐based livestock) is high in salt and low in fiber At present in Western diet the ratio of arachidonic acid (ARA) to docosa-hexaenoic acid (DHA) is about 201 By contrast the Paleolithic diet (stone‐age diet) on which our forefathers lived and survived throughout their his-tory contained high amounts of fresh fruits green vegetables lean meats fish seeds piths and barks with ARA to DHA ratio of 11 Long‐term con-sumption of Western diet produces detrimental effect on health not only by inducing an increase in systemic and brain inflammation and oxidative stress through the stimulation of insulin‐like growth factor 1 (IGF‐1) and Toll‐like receptors and generation of high levels of ARA‐derived lipid mediators but also by mediating abnormalities in mitochondrial function along with the induction of

insulin resistance and leptin resistance in visceral organs and the brain The onset and induction of oxidative stress neuroinflammation and abnormal-ities in mitochondrial function are closely associated with impairments in frontal limbic and hippocampal systems leading to changes in learning memory cognition and hedonics In visceral tissues oxidative stress and inflammation along with genetic and environmental factors promote obesity diabetes metabolic syndrome heart disease and cancer These pathological conditions are risk factors for neurological disorders (stroke AD and depression) Thus incidences of neurological disorders are two‐ to threefold higher in patients with type 2 diabetes metabolic syndrome and cardiovascular diseases compared to normal subjects of the same age

The Mediterranean diet which is enriched in fruits vegetables garlic legumes and unrefined cereals and has moderate amount of fish and high amount of olive oil along with modest intake of red wine produces anti‐inflammatory antioxidant and antidiabetic effects leading to cardio‐ and neuroprotection in heart disease and neurological disorders

Exercise initiates the maintenance of good car-diorespiratory cardiovascular cerebrovascular and muscular fitness by preventing metabolic imbalance increasing energy consumption improving insulin sensitivity increasing blood flow elevating levels of brain‐derived neurotrophic factor reducing inflammation and enhancing learning and memory

PREFACE

xx PREFACE

Good nutrition daily exercise and adequate sleep are the foundations for maintaining optimal health

Information on diet and exercise is scattered throughout the literature in the form of original papers reviews and some books These books describe the effects of diet and exercise on visceral organs The purpose of this edited book is to pro-vide readers with a comprehensive and cutting‐edge information on the effects of diet and exercise on cognitive function and age‐related visceral and brain diseases in a manner which is useful not only to students and teachers but also to researchers dietitians nutritionists exercise physiologists and physicians To the best of our knowledge this edited book will be the first to provide a comprehensive description of signal transduction processes associated with the effects of diet and exercise on the cognitive function

This edited book has 28 chapters Chapters 1ndash9 describe the effects of various diet patterns on metabolic changes in visceral organs and the brain Chapters 10ndash26 provide information on the effects of diet and exercise on cognitive function and age‐related neurological disorders Chapter 27 deals

with the role of salt in the pathogenesis of dementia and stroke Finally Chapter 28 deals with perspective on the current progress that will be important for future studies on the effects of diet and exercise on cognitive function in normal subjects and age‐related neurological disorders

Our contributors have tried to ensure uniformity and mode of presentation simple and we have made sure that the progression of subject matter from one topic to another is logical Each chapter provides an extensive bibliography for readers to consult For the sake of simplicity and uniformity a large number of figures with chemical structures of metabolites along with line diagrams of colored signal transduction pathways are included We hope that our attempt to integrate and consolidate the knowledge on the effects of diet and exercise on cognitive function will initiate more studies on molecular mechanisms that link among diet and exercise with cognitive function in normal subjects and patients with age‐related neu-rological disorders

Tahira Farooqui Akhlaq A Farooqui

We thank all the authors of this book who shared their expertise by contributing chapters of a high standard thus making our editorial task much easier We are grateful to Justin Jeffryes Editorial Director at Wiley‐Blackwell for his cooperation and patience during this process We are also

thankful to Stephanie Dollan Senior Editorial Assistant at Wiley‐Blackwell for her professional handling of the manuscript

Tahira FarooquiAkhlaq A Farooqui

ACKNOWLEDGMENTS

Diet and Exercise in Cognitive Function and Neurological Diseases First Edition Edited by Tahira Farooqui and Akhlaq A Farooqui copy 2015 John Wiley amp Sons Inc Published 2015 by John Wiley amp Sons Inc

11 INTRODUCTION

Nutritionndashgene interactions play a pivotal role in cognitive function and neurological disease throughout life Nutrition is one of many environ-mental factors that profoundly alter the phenotypic expression of a given genotype with major impli-cations for development metabolism health and disease [1ndash4] These effects are mediated by changes in expression of multiple genes and can involve epigenetic mechanisms nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence Responses to nutrition are in turn affected by individual genetic variability The effects of nutrition on gene expression are exerted throughout the life cycle with prenatal and early postnatal life being especially critical periods for optimal development Changes in gene expression may be dynamic and short term stable and long term and even heritable between cell divisions and across generations

This review focuses on the following key topics First a short overview is provided on the role of nutrition in cognitive neuroscience Second mecha-nisms underlying nutritionndashgene interactions are discussed especially in relation to the roles of epige-netics and genetic variability in neuroscience

Third attention is focused on the importance of environment and epigenetics in neurological health and disease Finally the role of early nutrition in brain development and later neurological disease is addressed Overall this review highlights the criti-cal importance of nutritionndashgene interactions to optimal neurological function and prevention and treatment of multiple neurological disorders

12 NUTRITION AND COGNITIVE NEUROSCIENCE

The role of nutrition in cognitive neuroscience is highly complex because as with all aspects of nutrition it is multifactorial It is not concerned simply with the impact of a single chemical on the brain but with numerous interactions between multiple nutrients metabolites food and other environmental and genetic factors Nevertheless considerable evidence now links many aspects of nutrition with cognition mental health and well‐being neurological dysfunction and disease [1ndash9] Protective roles are suggested for the Mediterranean diet optimal energy status fish fruits vegetables polyphenols omega‐3 polyunsaturated fatty acids iron zinc copper and numerous vitamins

NUTRITION GENES AND NEUROSCIENCE IMPLICATIONS FOR DEVELOPMENT HEALTH AND DISEASE

Margaret Joy DaunceyWolfson College University of Cambridge Cambridge UK

1

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

Contents ix

26 Exercise‐Induced Protection Against Aging and Neurodegenerative Diseases Role of Redox‐ and Mitochondrial‐Based Alterations 309Inecircs Marques‐Aleixo Estela Santos‐Alves Paula I Moreira Paulo J Oliveira Joseacute Magalhatildees and Antoacutenio Ascensatildeo

27 Exercise Neuroplasticity and Growth Factors in Adolescence 323Helios Pareja‐Galeano Sara Mayero and Fabiaacuten Sanchis‐Gomar

28 Summary Perspective and Direction for Future Studies 339Tahira Farooqui and Akhlaq A Farooqui

Index 349

Abdullah S Alhomida Department of Biochem-istry College of Science King Saud University Riyadh Saudi Arabia

Trevor Archer Department of Psychology University of Gothenburg Gothenburg Sweden Network for Empowerment and Well‐Being Gothenburg Sweden

Antoacutenio Ascensatildeo Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Jimmy D Bell Department of Life Sciences Clipstone Building University of Westminster London UK

Caren Bernardi Programa de Poacutes-Graduaccedilatildeo Ciecircncias da Reabilitaccedilatildeo Universidade Federal de Ciecircncias da Sauacutede de Porto Alegre Porto Alegre Brazil

Richard Bloch Department of Psychiatry and Behavioral Medicine Brody School of Medicine at East Carolina University Greenville NC USA

Virginia Boccardi Department of Internal Medicine Surgical Neurological Metabolic Disease and Geriatric Medicine Second University of Naples Naples Italy

Marialaura Bonaccio Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Mario Roberto Generosi Brauner Escola de Educaccedilatildeo Fiacutesica (ESEF) Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Michael J Chen Department of Biological Sciences California State University Los Angeles CA USA

Undurti N Das UND Life Sciences Federal Way WA USA

Margaret Joy Dauncey Wolfson College University of Cambridge Cambridge UK

Abeer M Eissa Psychogeriatric Research Center Department of Psychiatry School of Medicine Ain Shams University Cairo Egypt

Kirk I Erickson Department of Psychology University of Pittsburgh Pittsburgh PA USA

Akhlaq A Farooqui Department of Molecular and Cellular Biochemistry College of Medicine The Ohio State University Columbus OH USA

Tahira Farooqui Department of Molecular and Cellular Biochemistry College of Medicine The Ohio State University Columbus OH USA

CoNTRIBUToRS

xii Contributors

Heather M Francis School of Psychology Science Department University of New South Wales Sydney New South Wales Australia

Dorota Frydecka Department and Clinic of Psychiatry Wrocław Medical University Wrocław Poland

Giovanni de Gaetano Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Danilo Garcia Network for Empowerment and Well‐Being Gothenburg Sweden Center for Ethics Law and Mental Health University of Gothenburg Gothenburg Sweden

Nicola J Gates School of Psychiatry Centre for Healthy Brain Ageing (CheBA) University of New South Wales Sydney New South Wales Australia Brain and Mind Psychology Sydney New South Wales Australia

Dmitry Gerashchenko Department of Psychiatry Harvard Medical School and Veterans Affairs Boston Healthcare System West Roxbury MA USA

Carlos Alberto Gonccedilalves Programa de Poacutes- Graduaccedilatildeo Ciecircncias da Reabilitaccedilatildeo Universi-dade Federal de Ciecircncias da Sauacutede de Porto Alegre Porto Alegre Brazil Departamento de Bioquiacutemica Instituto de Ciecircncias Baacutesicas da Sauacutede Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Geoffrey W Guy GW Pharmaceuticals Porton Down Salisbury Wiltshire UK

Christa W Habela Division of Child Neurology Department of Neurology The Johns Hopkins School of Medicine Baltimore MD USA

A Garrett Hazelton Department of Psychiatry and Behavioral Medicine Brody School of Med-icine at East Carolina University Greenville NC USA

Doaa H Hewedi Psychogeriatric Research Center Department of Psychiatry School of Medicine Ain Shams University Cairo Egypt

Licia Iacoviello Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Ryuta Kawashima Smart Ageing International Research Centre Institute of Development Aging and Cancer Tohoku University Sendai Japan

Haseeb A Khan Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia

Eric H Kossoff Division of Child Neurology Department of Neurology The Johns Hopkins School of Medicine Baltimore MD USA

Edwin D Lephart Department of Physiology and Developmental Biology and The Neuroscience Center College of Life Sciences Brigham Young University Provo UT USA

Adrian l Lopresti School of Psychology and Exercise Science Murdoch University Murdoch Western Australia Australia

Joseacute Magalhatildees Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Inecircs Marques‐Aleixo Research Center in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Bonita L Marks Departments of Exercise and Sport Science Emergency Medicine and Allied Health Sciences University of North Carolina at Chapel Hill Chapel Hill NC USA

Sara Mayero Department of Psychiatry Hospital Moncloa Madrid Spain

Błazej Misiak Department and Clinic of Psychiatry Wrocław Medical University Wrocław Poland Department of Genetics Wrocław Medical University Wrocław Poland

Paula I Moreira Centre for Neuroscience and Cell Biology (CNC) UC‐BiotechBiocant Park University of Coimbra Cantanhede Portugal Institute of Physiology Faculty of Medicine University of Coimbra Coimbra Portugal

Ahmed A Moustafa School of Social Sciences and Psychology amp Marcs Institute for Brain and Behaviour University of Western Sydney Sydney New South Wales Australia

Shin Murakami Department of Basic Sciences College of Osteopathic Medicine Touro Univer-sity‐California Mare Island Vallejo CA USA

Bijli Nanda Department of Physiology School of Medical Sciences and Research Sharda University Greater Noida Uttar Pradesh India

Shantanu R Neravetla Medical Director Heart Health Now LLC Springfield OH USA

Contributors xiii

Surender R Neravetla Director Cardiac Surgery Springfield Regional Medical Center Spring-field OH USA Wright State University Dayton OH USA

Rui Nouchi Human and Social Response Research Division International Research Institute of Disaster Science Tohoku University Sendai Japan Smart Ageing International Research Centre Institute of Development Aging and Cancer Tohoku University Sendai Japan

Alistair VW Nunn School of Pharmacy Uni-versity of Reading Reading UK

Mohammad Shamsul ola Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia

Paulo J oliveira Centre for Neuroscience and Cell Biology (CNC) UC‐BiotechBiocant Park University of Coimbra Cantanhede Portugal

Kanti Bhooshan Pandey Department of Biochemistry University of Allahabad Allahabad Uttar Pradesh India

Giuseppe Paolisso Department of Internal Medi-cine Surgical Neurological Metabolic Dis-ease and Geriatric Medicine Second University of Naples Naples Italy

Helios Pareja‐Galeano Department of Physiology School of Medicine University of Valencia Valencia Spain Fundacioacuten del Hospital Cliacutenico Universitario Valencia (FIHCUV‐ INCLIVA) Valencia Spain

Syed Ibrahim Rizvi Department of Biochemistry University of Allahabad Allahabad Uttar Pradesh India

Sy Saeed Department of Psychiatry and Behavioral Medicine Brody School of Medicine at East Carolina University Greenville NC USA

Fabiaacuten Sanchis‐Gomar Department of Physiology School of Medicine University of Valencia Valencia Spain Fundacioacuten del Hospital Cliacutenico Universitario Valencia (FIHCUV‐INCLIVA) Valencia Spain

Estela Santos‐Alves Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

S Manjunatha Endocrine Research Unit Mayo Clinic College of Medicine Rochester MN USA

Maria Fiatarone Singh Exercise Health and Performance Faculty Research Group Sydney Medical School The University of Sydney Lid-combe New South Wales Australia Hebrew SeniorLife Boston MA USA Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University Boston MA USA

Patsri Srisuwan Outpatient and Family Medicine Department Phramongkutklao Hospital and College of Medicine Bangkok Thailand

Richard J Stevenson Department of Psychology Macquarie University Sydney New South Wales Australia

Mark R Zielinski Department of Psychiatry Harvard Medical School and Veterans Affairs Boston Healthcare System West Roxbury MA USA

FoREWoRD

the brain is a plastic organ that is continuously changing and adapting to its environment because of this natural capacity for plasticity there has been an increasing interest from both scientific and public policy groups to attempt to leverage brain plasticity to prevent or treat neurological and psy-chiatric conditions From this perspective there have emerged three categories of treatments that attempt to take advantage of brain plasticity First there are traditional pharmaceutical treatments that try to manipulate the molecular milieu of the brain through medication thereby influencing the prevalence and trajectory of brain disorders unfortunately effective pharmaceutical treatments with minimal side effects and high compliance rates have remained elusive for many disorders of the brain thus in contrast to pharmaceutical approaches the other two approaches are nonphar-maceutical in nature and include (1) behavioral therapies (eg cognitive behavioral therapy) and (2) lifestyle changes (eg exercise habits) these two approaches are often referred to as ldquononpharmaceuti-calrdquo in the sense that they are not medication based However the term ldquononpharmaceuticalrdquo should not be confused with ldquononpharmacologicalrdquo indeed behavioral and lifestyle treatments are methods of manipulating the endogenous pharmacology of the brain

over the past decade there has been an explosion of scientific interest in ldquononpharmaceuticalrdquo approaches to brain plasticity especially those

approaches that include lifestyles (eg exercise habits) this body of work emerges within the context of a well‐established research demonstrating the impact of health behaviors on the function and integrity of visceral organs and physical health Amazingly it has been only relatively recently that the brain and its functions (eg cognition) have been considered as being closely linked to health behaviors such as physical activity and dietary habits indeed as the chapters in this book discuss the brain and its functions are highly susceptible to the same types of decay and dysfunction from engagement in unhealthy lifestyles as the rest of the body Fortunately massive amounts of research have now clearly demonstrated the importance of dietary and exercise habits with cognitive and brain function or diseases and suggest that these effects of unhealthy behaviors on the brain are modifiable For example the work by our group found that engagement in moderate‐intensity exercise several days a week for 1 year was sufficient for increasing the size of the hippocampus in a sample of cognitively healthy but sedentary elderly [1] interestingly the change in hippocampal volume was correlated with changes in spatial memory performance for the exercise group and not for the control group indicating that the changes in hippocampal volume were not a mean-ingless by‐product of greater exercise participation but rather that they had significant implications for cognitive function such findings indicate not only that the brain remains plastic but also that

xvi Foreword

engagement in exercise has the capability of modi-fying the structural integrity of the brain Many other studies have also reported similar effects of exercise physical activity and fitness on biomarkers brain health and cognitive function

As will be described throughout this book despite some consensus on the importance of exercise and dietary lifestyles for brain function there remains debate about the mechanisms the dosendashresponse and the extent to which these life-style choices are effective for both primary and secondary prevention of disease and long‐term treatment for the attenuation of cognitive or brain losses it will be necessary for well‐controlled randomized trials and longitudinal studies with larger sample sizes to more conclusively link these lifestyle approaches to improvements in cognitive and brain health Yet despite this need there is a growing consensus that dietary and exercise habits are important modifiable behaviors that directly influence cognitive and brain health throughout the lifespan the focus of this book titled Diet and

Exercise in Cognitive Function and Neurological Diseases addresses these topics and presents a timely and comprehensive review from world experts in neuroscience epidemiology neurology cognitive psychology nutrition genetics and exercise science this book will provide an excel-lent resource for students and researchers and serve as a guide for the development of future research projects and for the integration of health behaviors into clinical practice and public policies that strive to enhance cognitive and brain health

REFERENCE

1 erickson Ki et al exercise training increases size of hippocampus and improves memory Proc Natl Acad Sci U S A 2011 108(7) pp 3017ndash22

Kirk i erickson

Department of Psychology University of Pittsburgh

Pittsburgh PA USA

this is my warm welcome to the world of ldquodiet and exercise in cognitive function and neurological diseasesrdquo eating food and exercise are two fundamental activities in animal species they use three macronutrients for energy including carbohy-drates proteins and fatty acids Although the world Health organization (wHo) prioritizes ldquostopping hungerrdquo as a highest priority overnu-trition clearly is a concern on numerous health problems in the united states our body does not have positive mechanisms to remove overnu-trition which is why exercise has been a major intervention in order to reduce energy that is taken too much

the central nervous system (Cns) is a hungry tissue for energy it needs energy for a wide variety of functions and therefore when metabolic path-ways are altered Cns is in a big trouble in diabetes high glucose in the blood is characteristic due to deficits in insulin or insulin pathways the Alzheimerrsquos disease (Ad) which is a major cause of dementia shares characteristics of diabetes in the brainmdashit has been proposed to be classified as ldquotype 3 diabetesrdquo in Ad some neurons cannot take glucose inside as well as cannot use the secondary energy source neither with abundant glucose the body thinks why we should use the second energy source ketone bodies (and it does not use ketone

bodies) to turn the situation better glucose levels should be lower so that the neurons start to use ketone bodies

in Ad and some neurological diseases reducing glucose seems to be an effective strategy to provide the secondary energy to the neurons Low‐carbohydrate (low‐carb) diet has a direct effect on reducing glucose and importantly reducing insulin we now know reducing iGF‐1insulin signal can extend lifespan in a wide variety of species from worms to flies and to mammals Low‐carb diet may have a beneficial effect on extending lifespan

Ketogenic diet uses low carb to reduce glucose and high lipids to provide ketone bodies which is a promising treatment in the future Ketogenic diet has originally been used for the treatment of a neurological disease epilepsy However it needs a caution about complex effects of lipids some of which have negative effects on patients with cardiovascular diseases it is essential to shift the diet strategy to the lipids that have neutral or beneficial effects on the health Applications of the diet to diabetes and Ad have been considered

this book will provide a nicely blended over-view of diet and exercise it has chapters describing various types of diet including among

FoREWoRD

xviii Foreword

others ketogenic diet Mediterranean diet and n‐3 (omega‐3) diet other chapters describe a wide variety of benefits on exercise some toxic nutritional metabolites are also getting attention including homocysteine which is linked to methi-onine metabolism Methionine together with folic acidvitamin b12 has been implicated to play a role in normal aging

i would like to thank the editors for the opportunity to write Foreword of this exciting book

shin Murakami Phd

Department of Basic Sciences College of Osteopathic Medicine

Touro University California Vallejo CA USA

Diet and exercise play an important role in maintaining good cognitive function and longevity Macro‐ and micronutrients not only provide energy and building material to the body but also have ability to prevent and protect against age‐related neurological disor-ders Exercise initiates the maintenance of good cardiorespiratory cardiovascular cerebrovascular and muscular fitness by increasing energy con-sumption improving insulin sensitivity increasing blood flow increasing the expression of brain‐derived neurotrophic factor and reducing inflammation Western diet which is enriched in refined carbohy-drates (simple sugars) partially hydrogenated oils (peanut corn soybean and canola) and proteins of animal origin (enriched in corn‐based livestock) is high in salt and low in fiber At present in Western diet the ratio of arachidonic acid (ARA) to docosa-hexaenoic acid (DHA) is about 201 By contrast the Paleolithic diet (stone‐age diet) on which our forefathers lived and survived throughout their his-tory contained high amounts of fresh fruits green vegetables lean meats fish seeds piths and barks with ARA to DHA ratio of 11 Long‐term con-sumption of Western diet produces detrimental effect on health not only by inducing an increase in systemic and brain inflammation and oxidative stress through the stimulation of insulin‐like growth factor 1 (IGF‐1) and Toll‐like receptors and generation of high levels of ARA‐derived lipid mediators but also by mediating abnormalities in mitochondrial function along with the induction of

insulin resistance and leptin resistance in visceral organs and the brain The onset and induction of oxidative stress neuroinflammation and abnormal-ities in mitochondrial function are closely associated with impairments in frontal limbic and hippocampal systems leading to changes in learning memory cognition and hedonics In visceral tissues oxidative stress and inflammation along with genetic and environmental factors promote obesity diabetes metabolic syndrome heart disease and cancer These pathological conditions are risk factors for neurological disorders (stroke AD and depression) Thus incidences of neurological disorders are two‐ to threefold higher in patients with type 2 diabetes metabolic syndrome and cardiovascular diseases compared to normal subjects of the same age

The Mediterranean diet which is enriched in fruits vegetables garlic legumes and unrefined cereals and has moderate amount of fish and high amount of olive oil along with modest intake of red wine produces anti‐inflammatory antioxidant and antidiabetic effects leading to cardio‐ and neuroprotection in heart disease and neurological disorders

Exercise initiates the maintenance of good car-diorespiratory cardiovascular cerebrovascular and muscular fitness by preventing metabolic imbalance increasing energy consumption improving insulin sensitivity increasing blood flow elevating levels of brain‐derived neurotrophic factor reducing inflammation and enhancing learning and memory

PREFACE

xx PREFACE

Good nutrition daily exercise and adequate sleep are the foundations for maintaining optimal health

Information on diet and exercise is scattered throughout the literature in the form of original papers reviews and some books These books describe the effects of diet and exercise on visceral organs The purpose of this edited book is to pro-vide readers with a comprehensive and cutting‐edge information on the effects of diet and exercise on cognitive function and age‐related visceral and brain diseases in a manner which is useful not only to students and teachers but also to researchers dietitians nutritionists exercise physiologists and physicians To the best of our knowledge this edited book will be the first to provide a comprehensive description of signal transduction processes associated with the effects of diet and exercise on the cognitive function

This edited book has 28 chapters Chapters 1ndash9 describe the effects of various diet patterns on metabolic changes in visceral organs and the brain Chapters 10ndash26 provide information on the effects of diet and exercise on cognitive function and age‐related neurological disorders Chapter 27 deals

with the role of salt in the pathogenesis of dementia and stroke Finally Chapter 28 deals with perspective on the current progress that will be important for future studies on the effects of diet and exercise on cognitive function in normal subjects and age‐related neurological disorders

Our contributors have tried to ensure uniformity and mode of presentation simple and we have made sure that the progression of subject matter from one topic to another is logical Each chapter provides an extensive bibliography for readers to consult For the sake of simplicity and uniformity a large number of figures with chemical structures of metabolites along with line diagrams of colored signal transduction pathways are included We hope that our attempt to integrate and consolidate the knowledge on the effects of diet and exercise on cognitive function will initiate more studies on molecular mechanisms that link among diet and exercise with cognitive function in normal subjects and patients with age‐related neu-rological disorders

Tahira Farooqui Akhlaq A Farooqui

We thank all the authors of this book who shared their expertise by contributing chapters of a high standard thus making our editorial task much easier We are grateful to Justin Jeffryes Editorial Director at Wiley‐Blackwell for his cooperation and patience during this process We are also

thankful to Stephanie Dollan Senior Editorial Assistant at Wiley‐Blackwell for her professional handling of the manuscript

Tahira FarooquiAkhlaq A Farooqui

ACKNOWLEDGMENTS

Diet and Exercise in Cognitive Function and Neurological Diseases First Edition Edited by Tahira Farooqui and Akhlaq A Farooqui copy 2015 John Wiley amp Sons Inc Published 2015 by John Wiley amp Sons Inc

11 INTRODUCTION

Nutritionndashgene interactions play a pivotal role in cognitive function and neurological disease throughout life Nutrition is one of many environ-mental factors that profoundly alter the phenotypic expression of a given genotype with major impli-cations for development metabolism health and disease [1ndash4] These effects are mediated by changes in expression of multiple genes and can involve epigenetic mechanisms nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence Responses to nutrition are in turn affected by individual genetic variability The effects of nutrition on gene expression are exerted throughout the life cycle with prenatal and early postnatal life being especially critical periods for optimal development Changes in gene expression may be dynamic and short term stable and long term and even heritable between cell divisions and across generations

This review focuses on the following key topics First a short overview is provided on the role of nutrition in cognitive neuroscience Second mecha-nisms underlying nutritionndashgene interactions are discussed especially in relation to the roles of epige-netics and genetic variability in neuroscience

Third attention is focused on the importance of environment and epigenetics in neurological health and disease Finally the role of early nutrition in brain development and later neurological disease is addressed Overall this review highlights the criti-cal importance of nutritionndashgene interactions to optimal neurological function and prevention and treatment of multiple neurological disorders

12 NUTRITION AND COGNITIVE NEUROSCIENCE

The role of nutrition in cognitive neuroscience is highly complex because as with all aspects of nutrition it is multifactorial It is not concerned simply with the impact of a single chemical on the brain but with numerous interactions between multiple nutrients metabolites food and other environmental and genetic factors Nevertheless considerable evidence now links many aspects of nutrition with cognition mental health and well‐being neurological dysfunction and disease [1ndash9] Protective roles are suggested for the Mediterranean diet optimal energy status fish fruits vegetables polyphenols omega‐3 polyunsaturated fatty acids iron zinc copper and numerous vitamins

NUTRITION GENES AND NEUROSCIENCE IMPLICATIONS FOR DEVELOPMENT HEALTH AND DISEASE

Margaret Joy DaunceyWolfson College University of Cambridge Cambridge UK

1

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

Abdullah S Alhomida Department of Biochem-istry College of Science King Saud University Riyadh Saudi Arabia

Trevor Archer Department of Psychology University of Gothenburg Gothenburg Sweden Network for Empowerment and Well‐Being Gothenburg Sweden

Antoacutenio Ascensatildeo Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Jimmy D Bell Department of Life Sciences Clipstone Building University of Westminster London UK

Caren Bernardi Programa de Poacutes-Graduaccedilatildeo Ciecircncias da Reabilitaccedilatildeo Universidade Federal de Ciecircncias da Sauacutede de Porto Alegre Porto Alegre Brazil

Richard Bloch Department of Psychiatry and Behavioral Medicine Brody School of Medicine at East Carolina University Greenville NC USA

Virginia Boccardi Department of Internal Medicine Surgical Neurological Metabolic Disease and Geriatric Medicine Second University of Naples Naples Italy

Marialaura Bonaccio Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Mario Roberto Generosi Brauner Escola de Educaccedilatildeo Fiacutesica (ESEF) Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Michael J Chen Department of Biological Sciences California State University Los Angeles CA USA

Undurti N Das UND Life Sciences Federal Way WA USA

Margaret Joy Dauncey Wolfson College University of Cambridge Cambridge UK

Abeer M Eissa Psychogeriatric Research Center Department of Psychiatry School of Medicine Ain Shams University Cairo Egypt

Kirk I Erickson Department of Psychology University of Pittsburgh Pittsburgh PA USA

Akhlaq A Farooqui Department of Molecular and Cellular Biochemistry College of Medicine The Ohio State University Columbus OH USA

Tahira Farooqui Department of Molecular and Cellular Biochemistry College of Medicine The Ohio State University Columbus OH USA

CoNTRIBUToRS

xii Contributors

Heather M Francis School of Psychology Science Department University of New South Wales Sydney New South Wales Australia

Dorota Frydecka Department and Clinic of Psychiatry Wrocław Medical University Wrocław Poland

Giovanni de Gaetano Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Danilo Garcia Network for Empowerment and Well‐Being Gothenburg Sweden Center for Ethics Law and Mental Health University of Gothenburg Gothenburg Sweden

Nicola J Gates School of Psychiatry Centre for Healthy Brain Ageing (CheBA) University of New South Wales Sydney New South Wales Australia Brain and Mind Psychology Sydney New South Wales Australia

Dmitry Gerashchenko Department of Psychiatry Harvard Medical School and Veterans Affairs Boston Healthcare System West Roxbury MA USA

Carlos Alberto Gonccedilalves Programa de Poacutes- Graduaccedilatildeo Ciecircncias da Reabilitaccedilatildeo Universi-dade Federal de Ciecircncias da Sauacutede de Porto Alegre Porto Alegre Brazil Departamento de Bioquiacutemica Instituto de Ciecircncias Baacutesicas da Sauacutede Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Geoffrey W Guy GW Pharmaceuticals Porton Down Salisbury Wiltshire UK

Christa W Habela Division of Child Neurology Department of Neurology The Johns Hopkins School of Medicine Baltimore MD USA

A Garrett Hazelton Department of Psychiatry and Behavioral Medicine Brody School of Med-icine at East Carolina University Greenville NC USA

Doaa H Hewedi Psychogeriatric Research Center Department of Psychiatry School of Medicine Ain Shams University Cairo Egypt

Licia Iacoviello Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Ryuta Kawashima Smart Ageing International Research Centre Institute of Development Aging and Cancer Tohoku University Sendai Japan

Haseeb A Khan Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia

Eric H Kossoff Division of Child Neurology Department of Neurology The Johns Hopkins School of Medicine Baltimore MD USA

Edwin D Lephart Department of Physiology and Developmental Biology and The Neuroscience Center College of Life Sciences Brigham Young University Provo UT USA

Adrian l Lopresti School of Psychology and Exercise Science Murdoch University Murdoch Western Australia Australia

Joseacute Magalhatildees Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Inecircs Marques‐Aleixo Research Center in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Bonita L Marks Departments of Exercise and Sport Science Emergency Medicine and Allied Health Sciences University of North Carolina at Chapel Hill Chapel Hill NC USA

Sara Mayero Department of Psychiatry Hospital Moncloa Madrid Spain

Błazej Misiak Department and Clinic of Psychiatry Wrocław Medical University Wrocław Poland Department of Genetics Wrocław Medical University Wrocław Poland

Paula I Moreira Centre for Neuroscience and Cell Biology (CNC) UC‐BiotechBiocant Park University of Coimbra Cantanhede Portugal Institute of Physiology Faculty of Medicine University of Coimbra Coimbra Portugal

Ahmed A Moustafa School of Social Sciences and Psychology amp Marcs Institute for Brain and Behaviour University of Western Sydney Sydney New South Wales Australia

Shin Murakami Department of Basic Sciences College of Osteopathic Medicine Touro Univer-sity‐California Mare Island Vallejo CA USA

Bijli Nanda Department of Physiology School of Medical Sciences and Research Sharda University Greater Noida Uttar Pradesh India

Shantanu R Neravetla Medical Director Heart Health Now LLC Springfield OH USA

Contributors xiii

Surender R Neravetla Director Cardiac Surgery Springfield Regional Medical Center Spring-field OH USA Wright State University Dayton OH USA

Rui Nouchi Human and Social Response Research Division International Research Institute of Disaster Science Tohoku University Sendai Japan Smart Ageing International Research Centre Institute of Development Aging and Cancer Tohoku University Sendai Japan

Alistair VW Nunn School of Pharmacy Uni-versity of Reading Reading UK

Mohammad Shamsul ola Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia

Paulo J oliveira Centre for Neuroscience and Cell Biology (CNC) UC‐BiotechBiocant Park University of Coimbra Cantanhede Portugal

Kanti Bhooshan Pandey Department of Biochemistry University of Allahabad Allahabad Uttar Pradesh India

Giuseppe Paolisso Department of Internal Medi-cine Surgical Neurological Metabolic Dis-ease and Geriatric Medicine Second University of Naples Naples Italy

Helios Pareja‐Galeano Department of Physiology School of Medicine University of Valencia Valencia Spain Fundacioacuten del Hospital Cliacutenico Universitario Valencia (FIHCUV‐ INCLIVA) Valencia Spain

Syed Ibrahim Rizvi Department of Biochemistry University of Allahabad Allahabad Uttar Pradesh India

Sy Saeed Department of Psychiatry and Behavioral Medicine Brody School of Medicine at East Carolina University Greenville NC USA

Fabiaacuten Sanchis‐Gomar Department of Physiology School of Medicine University of Valencia Valencia Spain Fundacioacuten del Hospital Cliacutenico Universitario Valencia (FIHCUV‐INCLIVA) Valencia Spain

Estela Santos‐Alves Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

S Manjunatha Endocrine Research Unit Mayo Clinic College of Medicine Rochester MN USA

Maria Fiatarone Singh Exercise Health and Performance Faculty Research Group Sydney Medical School The University of Sydney Lid-combe New South Wales Australia Hebrew SeniorLife Boston MA USA Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University Boston MA USA

Patsri Srisuwan Outpatient and Family Medicine Department Phramongkutklao Hospital and College of Medicine Bangkok Thailand

Richard J Stevenson Department of Psychology Macquarie University Sydney New South Wales Australia

Mark R Zielinski Department of Psychiatry Harvard Medical School and Veterans Affairs Boston Healthcare System West Roxbury MA USA

FoREWoRD

the brain is a plastic organ that is continuously changing and adapting to its environment because of this natural capacity for plasticity there has been an increasing interest from both scientific and public policy groups to attempt to leverage brain plasticity to prevent or treat neurological and psy-chiatric conditions From this perspective there have emerged three categories of treatments that attempt to take advantage of brain plasticity First there are traditional pharmaceutical treatments that try to manipulate the molecular milieu of the brain through medication thereby influencing the prevalence and trajectory of brain disorders unfortunately effective pharmaceutical treatments with minimal side effects and high compliance rates have remained elusive for many disorders of the brain thus in contrast to pharmaceutical approaches the other two approaches are nonphar-maceutical in nature and include (1) behavioral therapies (eg cognitive behavioral therapy) and (2) lifestyle changes (eg exercise habits) these two approaches are often referred to as ldquononpharmaceuti-calrdquo in the sense that they are not medication based However the term ldquononpharmaceuticalrdquo should not be confused with ldquononpharmacologicalrdquo indeed behavioral and lifestyle treatments are methods of manipulating the endogenous pharmacology of the brain

over the past decade there has been an explosion of scientific interest in ldquononpharmaceuticalrdquo approaches to brain plasticity especially those

approaches that include lifestyles (eg exercise habits) this body of work emerges within the context of a well‐established research demonstrating the impact of health behaviors on the function and integrity of visceral organs and physical health Amazingly it has been only relatively recently that the brain and its functions (eg cognition) have been considered as being closely linked to health behaviors such as physical activity and dietary habits indeed as the chapters in this book discuss the brain and its functions are highly susceptible to the same types of decay and dysfunction from engagement in unhealthy lifestyles as the rest of the body Fortunately massive amounts of research have now clearly demonstrated the importance of dietary and exercise habits with cognitive and brain function or diseases and suggest that these effects of unhealthy behaviors on the brain are modifiable For example the work by our group found that engagement in moderate‐intensity exercise several days a week for 1 year was sufficient for increasing the size of the hippocampus in a sample of cognitively healthy but sedentary elderly [1] interestingly the change in hippocampal volume was correlated with changes in spatial memory performance for the exercise group and not for the control group indicating that the changes in hippocampal volume were not a mean-ingless by‐product of greater exercise participation but rather that they had significant implications for cognitive function such findings indicate not only that the brain remains plastic but also that

xvi Foreword

engagement in exercise has the capability of modi-fying the structural integrity of the brain Many other studies have also reported similar effects of exercise physical activity and fitness on biomarkers brain health and cognitive function

As will be described throughout this book despite some consensus on the importance of exercise and dietary lifestyles for brain function there remains debate about the mechanisms the dosendashresponse and the extent to which these life-style choices are effective for both primary and secondary prevention of disease and long‐term treatment for the attenuation of cognitive or brain losses it will be necessary for well‐controlled randomized trials and longitudinal studies with larger sample sizes to more conclusively link these lifestyle approaches to improvements in cognitive and brain health Yet despite this need there is a growing consensus that dietary and exercise habits are important modifiable behaviors that directly influence cognitive and brain health throughout the lifespan the focus of this book titled Diet and

Exercise in Cognitive Function and Neurological Diseases addresses these topics and presents a timely and comprehensive review from world experts in neuroscience epidemiology neurology cognitive psychology nutrition genetics and exercise science this book will provide an excel-lent resource for students and researchers and serve as a guide for the development of future research projects and for the integration of health behaviors into clinical practice and public policies that strive to enhance cognitive and brain health

REFERENCE

1 erickson Ki et al exercise training increases size of hippocampus and improves memory Proc Natl Acad Sci U S A 2011 108(7) pp 3017ndash22

Kirk i erickson

Department of Psychology University of Pittsburgh

Pittsburgh PA USA

this is my warm welcome to the world of ldquodiet and exercise in cognitive function and neurological diseasesrdquo eating food and exercise are two fundamental activities in animal species they use three macronutrients for energy including carbohy-drates proteins and fatty acids Although the world Health organization (wHo) prioritizes ldquostopping hungerrdquo as a highest priority overnu-trition clearly is a concern on numerous health problems in the united states our body does not have positive mechanisms to remove overnu-trition which is why exercise has been a major intervention in order to reduce energy that is taken too much

the central nervous system (Cns) is a hungry tissue for energy it needs energy for a wide variety of functions and therefore when metabolic path-ways are altered Cns is in a big trouble in diabetes high glucose in the blood is characteristic due to deficits in insulin or insulin pathways the Alzheimerrsquos disease (Ad) which is a major cause of dementia shares characteristics of diabetes in the brainmdashit has been proposed to be classified as ldquotype 3 diabetesrdquo in Ad some neurons cannot take glucose inside as well as cannot use the secondary energy source neither with abundant glucose the body thinks why we should use the second energy source ketone bodies (and it does not use ketone

bodies) to turn the situation better glucose levels should be lower so that the neurons start to use ketone bodies

in Ad and some neurological diseases reducing glucose seems to be an effective strategy to provide the secondary energy to the neurons Low‐carbohydrate (low‐carb) diet has a direct effect on reducing glucose and importantly reducing insulin we now know reducing iGF‐1insulin signal can extend lifespan in a wide variety of species from worms to flies and to mammals Low‐carb diet may have a beneficial effect on extending lifespan

Ketogenic diet uses low carb to reduce glucose and high lipids to provide ketone bodies which is a promising treatment in the future Ketogenic diet has originally been used for the treatment of a neurological disease epilepsy However it needs a caution about complex effects of lipids some of which have negative effects on patients with cardiovascular diseases it is essential to shift the diet strategy to the lipids that have neutral or beneficial effects on the health Applications of the diet to diabetes and Ad have been considered

this book will provide a nicely blended over-view of diet and exercise it has chapters describing various types of diet including among

FoREWoRD

xviii Foreword

others ketogenic diet Mediterranean diet and n‐3 (omega‐3) diet other chapters describe a wide variety of benefits on exercise some toxic nutritional metabolites are also getting attention including homocysteine which is linked to methi-onine metabolism Methionine together with folic acidvitamin b12 has been implicated to play a role in normal aging

i would like to thank the editors for the opportunity to write Foreword of this exciting book

shin Murakami Phd

Department of Basic Sciences College of Osteopathic Medicine

Touro University California Vallejo CA USA

Diet and exercise play an important role in maintaining good cognitive function and longevity Macro‐ and micronutrients not only provide energy and building material to the body but also have ability to prevent and protect against age‐related neurological disor-ders Exercise initiates the maintenance of good cardiorespiratory cardiovascular cerebrovascular and muscular fitness by increasing energy con-sumption improving insulin sensitivity increasing blood flow increasing the expression of brain‐derived neurotrophic factor and reducing inflammation Western diet which is enriched in refined carbohy-drates (simple sugars) partially hydrogenated oils (peanut corn soybean and canola) and proteins of animal origin (enriched in corn‐based livestock) is high in salt and low in fiber At present in Western diet the ratio of arachidonic acid (ARA) to docosa-hexaenoic acid (DHA) is about 201 By contrast the Paleolithic diet (stone‐age diet) on which our forefathers lived and survived throughout their his-tory contained high amounts of fresh fruits green vegetables lean meats fish seeds piths and barks with ARA to DHA ratio of 11 Long‐term con-sumption of Western diet produces detrimental effect on health not only by inducing an increase in systemic and brain inflammation and oxidative stress through the stimulation of insulin‐like growth factor 1 (IGF‐1) and Toll‐like receptors and generation of high levels of ARA‐derived lipid mediators but also by mediating abnormalities in mitochondrial function along with the induction of

insulin resistance and leptin resistance in visceral organs and the brain The onset and induction of oxidative stress neuroinflammation and abnormal-ities in mitochondrial function are closely associated with impairments in frontal limbic and hippocampal systems leading to changes in learning memory cognition and hedonics In visceral tissues oxidative stress and inflammation along with genetic and environmental factors promote obesity diabetes metabolic syndrome heart disease and cancer These pathological conditions are risk factors for neurological disorders (stroke AD and depression) Thus incidences of neurological disorders are two‐ to threefold higher in patients with type 2 diabetes metabolic syndrome and cardiovascular diseases compared to normal subjects of the same age

The Mediterranean diet which is enriched in fruits vegetables garlic legumes and unrefined cereals and has moderate amount of fish and high amount of olive oil along with modest intake of red wine produces anti‐inflammatory antioxidant and antidiabetic effects leading to cardio‐ and neuroprotection in heart disease and neurological disorders

Exercise initiates the maintenance of good car-diorespiratory cardiovascular cerebrovascular and muscular fitness by preventing metabolic imbalance increasing energy consumption improving insulin sensitivity increasing blood flow elevating levels of brain‐derived neurotrophic factor reducing inflammation and enhancing learning and memory

PREFACE

xx PREFACE

Good nutrition daily exercise and adequate sleep are the foundations for maintaining optimal health

Information on diet and exercise is scattered throughout the literature in the form of original papers reviews and some books These books describe the effects of diet and exercise on visceral organs The purpose of this edited book is to pro-vide readers with a comprehensive and cutting‐edge information on the effects of diet and exercise on cognitive function and age‐related visceral and brain diseases in a manner which is useful not only to students and teachers but also to researchers dietitians nutritionists exercise physiologists and physicians To the best of our knowledge this edited book will be the first to provide a comprehensive description of signal transduction processes associated with the effects of diet and exercise on the cognitive function

This edited book has 28 chapters Chapters 1ndash9 describe the effects of various diet patterns on metabolic changes in visceral organs and the brain Chapters 10ndash26 provide information on the effects of diet and exercise on cognitive function and age‐related neurological disorders Chapter 27 deals

with the role of salt in the pathogenesis of dementia and stroke Finally Chapter 28 deals with perspective on the current progress that will be important for future studies on the effects of diet and exercise on cognitive function in normal subjects and age‐related neurological disorders

Our contributors have tried to ensure uniformity and mode of presentation simple and we have made sure that the progression of subject matter from one topic to another is logical Each chapter provides an extensive bibliography for readers to consult For the sake of simplicity and uniformity a large number of figures with chemical structures of metabolites along with line diagrams of colored signal transduction pathways are included We hope that our attempt to integrate and consolidate the knowledge on the effects of diet and exercise on cognitive function will initiate more studies on molecular mechanisms that link among diet and exercise with cognitive function in normal subjects and patients with age‐related neu-rological disorders

Tahira Farooqui Akhlaq A Farooqui

We thank all the authors of this book who shared their expertise by contributing chapters of a high standard thus making our editorial task much easier We are grateful to Justin Jeffryes Editorial Director at Wiley‐Blackwell for his cooperation and patience during this process We are also

thankful to Stephanie Dollan Senior Editorial Assistant at Wiley‐Blackwell for her professional handling of the manuscript

Tahira FarooquiAkhlaq A Farooqui

ACKNOWLEDGMENTS

Diet and Exercise in Cognitive Function and Neurological Diseases First Edition Edited by Tahira Farooqui and Akhlaq A Farooqui copy 2015 John Wiley amp Sons Inc Published 2015 by John Wiley amp Sons Inc

11 INTRODUCTION

Nutritionndashgene interactions play a pivotal role in cognitive function and neurological disease throughout life Nutrition is one of many environ-mental factors that profoundly alter the phenotypic expression of a given genotype with major impli-cations for development metabolism health and disease [1ndash4] These effects are mediated by changes in expression of multiple genes and can involve epigenetic mechanisms nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence Responses to nutrition are in turn affected by individual genetic variability The effects of nutrition on gene expression are exerted throughout the life cycle with prenatal and early postnatal life being especially critical periods for optimal development Changes in gene expression may be dynamic and short term stable and long term and even heritable between cell divisions and across generations

This review focuses on the following key topics First a short overview is provided on the role of nutrition in cognitive neuroscience Second mecha-nisms underlying nutritionndashgene interactions are discussed especially in relation to the roles of epige-netics and genetic variability in neuroscience

Third attention is focused on the importance of environment and epigenetics in neurological health and disease Finally the role of early nutrition in brain development and later neurological disease is addressed Overall this review highlights the criti-cal importance of nutritionndashgene interactions to optimal neurological function and prevention and treatment of multiple neurological disorders

12 NUTRITION AND COGNITIVE NEUROSCIENCE

The role of nutrition in cognitive neuroscience is highly complex because as with all aspects of nutrition it is multifactorial It is not concerned simply with the impact of a single chemical on the brain but with numerous interactions between multiple nutrients metabolites food and other environmental and genetic factors Nevertheless considerable evidence now links many aspects of nutrition with cognition mental health and well‐being neurological dysfunction and disease [1ndash9] Protective roles are suggested for the Mediterranean diet optimal energy status fish fruits vegetables polyphenols omega‐3 polyunsaturated fatty acids iron zinc copper and numerous vitamins

NUTRITION GENES AND NEUROSCIENCE IMPLICATIONS FOR DEVELOPMENT HEALTH AND DISEASE

Margaret Joy DaunceyWolfson College University of Cambridge Cambridge UK

1

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

xii Contributors

Heather M Francis School of Psychology Science Department University of New South Wales Sydney New South Wales Australia

Dorota Frydecka Department and Clinic of Psychiatry Wrocław Medical University Wrocław Poland

Giovanni de Gaetano Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Danilo Garcia Network for Empowerment and Well‐Being Gothenburg Sweden Center for Ethics Law and Mental Health University of Gothenburg Gothenburg Sweden

Nicola J Gates School of Psychiatry Centre for Healthy Brain Ageing (CheBA) University of New South Wales Sydney New South Wales Australia Brain and Mind Psychology Sydney New South Wales Australia

Dmitry Gerashchenko Department of Psychiatry Harvard Medical School and Veterans Affairs Boston Healthcare System West Roxbury MA USA

Carlos Alberto Gonccedilalves Programa de Poacutes- Graduaccedilatildeo Ciecircncias da Reabilitaccedilatildeo Universi-dade Federal de Ciecircncias da Sauacutede de Porto Alegre Porto Alegre Brazil Departamento de Bioquiacutemica Instituto de Ciecircncias Baacutesicas da Sauacutede Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Geoffrey W Guy GW Pharmaceuticals Porton Down Salisbury Wiltshire UK

Christa W Habela Division of Child Neurology Department of Neurology The Johns Hopkins School of Medicine Baltimore MD USA

A Garrett Hazelton Department of Psychiatry and Behavioral Medicine Brody School of Med-icine at East Carolina University Greenville NC USA

Doaa H Hewedi Psychogeriatric Research Center Department of Psychiatry School of Medicine Ain Shams University Cairo Egypt

Licia Iacoviello Department of Epidemiology and Prevention IRCCS Istituto Neurologico Mediterraneo NEUROMED Pozzilli Italy

Ryuta Kawashima Smart Ageing International Research Centre Institute of Development Aging and Cancer Tohoku University Sendai Japan

Haseeb A Khan Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia

Eric H Kossoff Division of Child Neurology Department of Neurology The Johns Hopkins School of Medicine Baltimore MD USA

Edwin D Lephart Department of Physiology and Developmental Biology and The Neuroscience Center College of Life Sciences Brigham Young University Provo UT USA

Adrian l Lopresti School of Psychology and Exercise Science Murdoch University Murdoch Western Australia Australia

Joseacute Magalhatildees Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Inecircs Marques‐Aleixo Research Center in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

Bonita L Marks Departments of Exercise and Sport Science Emergency Medicine and Allied Health Sciences University of North Carolina at Chapel Hill Chapel Hill NC USA

Sara Mayero Department of Psychiatry Hospital Moncloa Madrid Spain

Błazej Misiak Department and Clinic of Psychiatry Wrocław Medical University Wrocław Poland Department of Genetics Wrocław Medical University Wrocław Poland

Paula I Moreira Centre for Neuroscience and Cell Biology (CNC) UC‐BiotechBiocant Park University of Coimbra Cantanhede Portugal Institute of Physiology Faculty of Medicine University of Coimbra Coimbra Portugal

Ahmed A Moustafa School of Social Sciences and Psychology amp Marcs Institute for Brain and Behaviour University of Western Sydney Sydney New South Wales Australia

Shin Murakami Department of Basic Sciences College of Osteopathic Medicine Touro Univer-sity‐California Mare Island Vallejo CA USA

Bijli Nanda Department of Physiology School of Medical Sciences and Research Sharda University Greater Noida Uttar Pradesh India

Shantanu R Neravetla Medical Director Heart Health Now LLC Springfield OH USA

Contributors xiii

Surender R Neravetla Director Cardiac Surgery Springfield Regional Medical Center Spring-field OH USA Wright State University Dayton OH USA

Rui Nouchi Human and Social Response Research Division International Research Institute of Disaster Science Tohoku University Sendai Japan Smart Ageing International Research Centre Institute of Development Aging and Cancer Tohoku University Sendai Japan

Alistair VW Nunn School of Pharmacy Uni-versity of Reading Reading UK

Mohammad Shamsul ola Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia

Paulo J oliveira Centre for Neuroscience and Cell Biology (CNC) UC‐BiotechBiocant Park University of Coimbra Cantanhede Portugal

Kanti Bhooshan Pandey Department of Biochemistry University of Allahabad Allahabad Uttar Pradesh India

Giuseppe Paolisso Department of Internal Medi-cine Surgical Neurological Metabolic Dis-ease and Geriatric Medicine Second University of Naples Naples Italy

Helios Pareja‐Galeano Department of Physiology School of Medicine University of Valencia Valencia Spain Fundacioacuten del Hospital Cliacutenico Universitario Valencia (FIHCUV‐ INCLIVA) Valencia Spain

Syed Ibrahim Rizvi Department of Biochemistry University of Allahabad Allahabad Uttar Pradesh India

Sy Saeed Department of Psychiatry and Behavioral Medicine Brody School of Medicine at East Carolina University Greenville NC USA

Fabiaacuten Sanchis‐Gomar Department of Physiology School of Medicine University of Valencia Valencia Spain Fundacioacuten del Hospital Cliacutenico Universitario Valencia (FIHCUV‐INCLIVA) Valencia Spain

Estela Santos‐Alves Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

S Manjunatha Endocrine Research Unit Mayo Clinic College of Medicine Rochester MN USA

Maria Fiatarone Singh Exercise Health and Performance Faculty Research Group Sydney Medical School The University of Sydney Lid-combe New South Wales Australia Hebrew SeniorLife Boston MA USA Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University Boston MA USA

Patsri Srisuwan Outpatient and Family Medicine Department Phramongkutklao Hospital and College of Medicine Bangkok Thailand

Richard J Stevenson Department of Psychology Macquarie University Sydney New South Wales Australia

Mark R Zielinski Department of Psychiatry Harvard Medical School and Veterans Affairs Boston Healthcare System West Roxbury MA USA

FoREWoRD

the brain is a plastic organ that is continuously changing and adapting to its environment because of this natural capacity for plasticity there has been an increasing interest from both scientific and public policy groups to attempt to leverage brain plasticity to prevent or treat neurological and psy-chiatric conditions From this perspective there have emerged three categories of treatments that attempt to take advantage of brain plasticity First there are traditional pharmaceutical treatments that try to manipulate the molecular milieu of the brain through medication thereby influencing the prevalence and trajectory of brain disorders unfortunately effective pharmaceutical treatments with minimal side effects and high compliance rates have remained elusive for many disorders of the brain thus in contrast to pharmaceutical approaches the other two approaches are nonphar-maceutical in nature and include (1) behavioral therapies (eg cognitive behavioral therapy) and (2) lifestyle changes (eg exercise habits) these two approaches are often referred to as ldquononpharmaceuti-calrdquo in the sense that they are not medication based However the term ldquononpharmaceuticalrdquo should not be confused with ldquononpharmacologicalrdquo indeed behavioral and lifestyle treatments are methods of manipulating the endogenous pharmacology of the brain

over the past decade there has been an explosion of scientific interest in ldquononpharmaceuticalrdquo approaches to brain plasticity especially those

approaches that include lifestyles (eg exercise habits) this body of work emerges within the context of a well‐established research demonstrating the impact of health behaviors on the function and integrity of visceral organs and physical health Amazingly it has been only relatively recently that the brain and its functions (eg cognition) have been considered as being closely linked to health behaviors such as physical activity and dietary habits indeed as the chapters in this book discuss the brain and its functions are highly susceptible to the same types of decay and dysfunction from engagement in unhealthy lifestyles as the rest of the body Fortunately massive amounts of research have now clearly demonstrated the importance of dietary and exercise habits with cognitive and brain function or diseases and suggest that these effects of unhealthy behaviors on the brain are modifiable For example the work by our group found that engagement in moderate‐intensity exercise several days a week for 1 year was sufficient for increasing the size of the hippocampus in a sample of cognitively healthy but sedentary elderly [1] interestingly the change in hippocampal volume was correlated with changes in spatial memory performance for the exercise group and not for the control group indicating that the changes in hippocampal volume were not a mean-ingless by‐product of greater exercise participation but rather that they had significant implications for cognitive function such findings indicate not only that the brain remains plastic but also that

xvi Foreword

engagement in exercise has the capability of modi-fying the structural integrity of the brain Many other studies have also reported similar effects of exercise physical activity and fitness on biomarkers brain health and cognitive function

As will be described throughout this book despite some consensus on the importance of exercise and dietary lifestyles for brain function there remains debate about the mechanisms the dosendashresponse and the extent to which these life-style choices are effective for both primary and secondary prevention of disease and long‐term treatment for the attenuation of cognitive or brain losses it will be necessary for well‐controlled randomized trials and longitudinal studies with larger sample sizes to more conclusively link these lifestyle approaches to improvements in cognitive and brain health Yet despite this need there is a growing consensus that dietary and exercise habits are important modifiable behaviors that directly influence cognitive and brain health throughout the lifespan the focus of this book titled Diet and

Exercise in Cognitive Function and Neurological Diseases addresses these topics and presents a timely and comprehensive review from world experts in neuroscience epidemiology neurology cognitive psychology nutrition genetics and exercise science this book will provide an excel-lent resource for students and researchers and serve as a guide for the development of future research projects and for the integration of health behaviors into clinical practice and public policies that strive to enhance cognitive and brain health

REFERENCE

1 erickson Ki et al exercise training increases size of hippocampus and improves memory Proc Natl Acad Sci U S A 2011 108(7) pp 3017ndash22

Kirk i erickson

Department of Psychology University of Pittsburgh

Pittsburgh PA USA

this is my warm welcome to the world of ldquodiet and exercise in cognitive function and neurological diseasesrdquo eating food and exercise are two fundamental activities in animal species they use three macronutrients for energy including carbohy-drates proteins and fatty acids Although the world Health organization (wHo) prioritizes ldquostopping hungerrdquo as a highest priority overnu-trition clearly is a concern on numerous health problems in the united states our body does not have positive mechanisms to remove overnu-trition which is why exercise has been a major intervention in order to reduce energy that is taken too much

the central nervous system (Cns) is a hungry tissue for energy it needs energy for a wide variety of functions and therefore when metabolic path-ways are altered Cns is in a big trouble in diabetes high glucose in the blood is characteristic due to deficits in insulin or insulin pathways the Alzheimerrsquos disease (Ad) which is a major cause of dementia shares characteristics of diabetes in the brainmdashit has been proposed to be classified as ldquotype 3 diabetesrdquo in Ad some neurons cannot take glucose inside as well as cannot use the secondary energy source neither with abundant glucose the body thinks why we should use the second energy source ketone bodies (and it does not use ketone

bodies) to turn the situation better glucose levels should be lower so that the neurons start to use ketone bodies

in Ad and some neurological diseases reducing glucose seems to be an effective strategy to provide the secondary energy to the neurons Low‐carbohydrate (low‐carb) diet has a direct effect on reducing glucose and importantly reducing insulin we now know reducing iGF‐1insulin signal can extend lifespan in a wide variety of species from worms to flies and to mammals Low‐carb diet may have a beneficial effect on extending lifespan

Ketogenic diet uses low carb to reduce glucose and high lipids to provide ketone bodies which is a promising treatment in the future Ketogenic diet has originally been used for the treatment of a neurological disease epilepsy However it needs a caution about complex effects of lipids some of which have negative effects on patients with cardiovascular diseases it is essential to shift the diet strategy to the lipids that have neutral or beneficial effects on the health Applications of the diet to diabetes and Ad have been considered

this book will provide a nicely blended over-view of diet and exercise it has chapters describing various types of diet including among

FoREWoRD

xviii Foreword

others ketogenic diet Mediterranean diet and n‐3 (omega‐3) diet other chapters describe a wide variety of benefits on exercise some toxic nutritional metabolites are also getting attention including homocysteine which is linked to methi-onine metabolism Methionine together with folic acidvitamin b12 has been implicated to play a role in normal aging

i would like to thank the editors for the opportunity to write Foreword of this exciting book

shin Murakami Phd

Department of Basic Sciences College of Osteopathic Medicine

Touro University California Vallejo CA USA

Diet and exercise play an important role in maintaining good cognitive function and longevity Macro‐ and micronutrients not only provide energy and building material to the body but also have ability to prevent and protect against age‐related neurological disor-ders Exercise initiates the maintenance of good cardiorespiratory cardiovascular cerebrovascular and muscular fitness by increasing energy con-sumption improving insulin sensitivity increasing blood flow increasing the expression of brain‐derived neurotrophic factor and reducing inflammation Western diet which is enriched in refined carbohy-drates (simple sugars) partially hydrogenated oils (peanut corn soybean and canola) and proteins of animal origin (enriched in corn‐based livestock) is high in salt and low in fiber At present in Western diet the ratio of arachidonic acid (ARA) to docosa-hexaenoic acid (DHA) is about 201 By contrast the Paleolithic diet (stone‐age diet) on which our forefathers lived and survived throughout their his-tory contained high amounts of fresh fruits green vegetables lean meats fish seeds piths and barks with ARA to DHA ratio of 11 Long‐term con-sumption of Western diet produces detrimental effect on health not only by inducing an increase in systemic and brain inflammation and oxidative stress through the stimulation of insulin‐like growth factor 1 (IGF‐1) and Toll‐like receptors and generation of high levels of ARA‐derived lipid mediators but also by mediating abnormalities in mitochondrial function along with the induction of

insulin resistance and leptin resistance in visceral organs and the brain The onset and induction of oxidative stress neuroinflammation and abnormal-ities in mitochondrial function are closely associated with impairments in frontal limbic and hippocampal systems leading to changes in learning memory cognition and hedonics In visceral tissues oxidative stress and inflammation along with genetic and environmental factors promote obesity diabetes metabolic syndrome heart disease and cancer These pathological conditions are risk factors for neurological disorders (stroke AD and depression) Thus incidences of neurological disorders are two‐ to threefold higher in patients with type 2 diabetes metabolic syndrome and cardiovascular diseases compared to normal subjects of the same age

The Mediterranean diet which is enriched in fruits vegetables garlic legumes and unrefined cereals and has moderate amount of fish and high amount of olive oil along with modest intake of red wine produces anti‐inflammatory antioxidant and antidiabetic effects leading to cardio‐ and neuroprotection in heart disease and neurological disorders

Exercise initiates the maintenance of good car-diorespiratory cardiovascular cerebrovascular and muscular fitness by preventing metabolic imbalance increasing energy consumption improving insulin sensitivity increasing blood flow elevating levels of brain‐derived neurotrophic factor reducing inflammation and enhancing learning and memory

PREFACE

xx PREFACE

Good nutrition daily exercise and adequate sleep are the foundations for maintaining optimal health

Information on diet and exercise is scattered throughout the literature in the form of original papers reviews and some books These books describe the effects of diet and exercise on visceral organs The purpose of this edited book is to pro-vide readers with a comprehensive and cutting‐edge information on the effects of diet and exercise on cognitive function and age‐related visceral and brain diseases in a manner which is useful not only to students and teachers but also to researchers dietitians nutritionists exercise physiologists and physicians To the best of our knowledge this edited book will be the first to provide a comprehensive description of signal transduction processes associated with the effects of diet and exercise on the cognitive function

This edited book has 28 chapters Chapters 1ndash9 describe the effects of various diet patterns on metabolic changes in visceral organs and the brain Chapters 10ndash26 provide information on the effects of diet and exercise on cognitive function and age‐related neurological disorders Chapter 27 deals

with the role of salt in the pathogenesis of dementia and stroke Finally Chapter 28 deals with perspective on the current progress that will be important for future studies on the effects of diet and exercise on cognitive function in normal subjects and age‐related neurological disorders

Our contributors have tried to ensure uniformity and mode of presentation simple and we have made sure that the progression of subject matter from one topic to another is logical Each chapter provides an extensive bibliography for readers to consult For the sake of simplicity and uniformity a large number of figures with chemical structures of metabolites along with line diagrams of colored signal transduction pathways are included We hope that our attempt to integrate and consolidate the knowledge on the effects of diet and exercise on cognitive function will initiate more studies on molecular mechanisms that link among diet and exercise with cognitive function in normal subjects and patients with age‐related neu-rological disorders

Tahira Farooqui Akhlaq A Farooqui

We thank all the authors of this book who shared their expertise by contributing chapters of a high standard thus making our editorial task much easier We are grateful to Justin Jeffryes Editorial Director at Wiley‐Blackwell for his cooperation and patience during this process We are also

thankful to Stephanie Dollan Senior Editorial Assistant at Wiley‐Blackwell for her professional handling of the manuscript

Tahira FarooquiAkhlaq A Farooqui

ACKNOWLEDGMENTS

Diet and Exercise in Cognitive Function and Neurological Diseases First Edition Edited by Tahira Farooqui and Akhlaq A Farooqui copy 2015 John Wiley amp Sons Inc Published 2015 by John Wiley amp Sons Inc

11 INTRODUCTION

Nutritionndashgene interactions play a pivotal role in cognitive function and neurological disease throughout life Nutrition is one of many environ-mental factors that profoundly alter the phenotypic expression of a given genotype with major impli-cations for development metabolism health and disease [1ndash4] These effects are mediated by changes in expression of multiple genes and can involve epigenetic mechanisms nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence Responses to nutrition are in turn affected by individual genetic variability The effects of nutrition on gene expression are exerted throughout the life cycle with prenatal and early postnatal life being especially critical periods for optimal development Changes in gene expression may be dynamic and short term stable and long term and even heritable between cell divisions and across generations

This review focuses on the following key topics First a short overview is provided on the role of nutrition in cognitive neuroscience Second mecha-nisms underlying nutritionndashgene interactions are discussed especially in relation to the roles of epige-netics and genetic variability in neuroscience

Third attention is focused on the importance of environment and epigenetics in neurological health and disease Finally the role of early nutrition in brain development and later neurological disease is addressed Overall this review highlights the criti-cal importance of nutritionndashgene interactions to optimal neurological function and prevention and treatment of multiple neurological disorders

12 NUTRITION AND COGNITIVE NEUROSCIENCE

The role of nutrition in cognitive neuroscience is highly complex because as with all aspects of nutrition it is multifactorial It is not concerned simply with the impact of a single chemical on the brain but with numerous interactions between multiple nutrients metabolites food and other environmental and genetic factors Nevertheless considerable evidence now links many aspects of nutrition with cognition mental health and well‐being neurological dysfunction and disease [1ndash9] Protective roles are suggested for the Mediterranean diet optimal energy status fish fruits vegetables polyphenols omega‐3 polyunsaturated fatty acids iron zinc copper and numerous vitamins

NUTRITION GENES AND NEUROSCIENCE IMPLICATIONS FOR DEVELOPMENT HEALTH AND DISEASE

Margaret Joy DaunceyWolfson College University of Cambridge Cambridge UK

1

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

Contributors xiii

Surender R Neravetla Director Cardiac Surgery Springfield Regional Medical Center Spring-field OH USA Wright State University Dayton OH USA

Rui Nouchi Human and Social Response Research Division International Research Institute of Disaster Science Tohoku University Sendai Japan Smart Ageing International Research Centre Institute of Development Aging and Cancer Tohoku University Sendai Japan

Alistair VW Nunn School of Pharmacy Uni-versity of Reading Reading UK

Mohammad Shamsul ola Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia

Paulo J oliveira Centre for Neuroscience and Cell Biology (CNC) UC‐BiotechBiocant Park University of Coimbra Cantanhede Portugal

Kanti Bhooshan Pandey Department of Biochemistry University of Allahabad Allahabad Uttar Pradesh India

Giuseppe Paolisso Department of Internal Medi-cine Surgical Neurological Metabolic Dis-ease and Geriatric Medicine Second University of Naples Naples Italy

Helios Pareja‐Galeano Department of Physiology School of Medicine University of Valencia Valencia Spain Fundacioacuten del Hospital Cliacutenico Universitario Valencia (FIHCUV‐ INCLIVA) Valencia Spain

Syed Ibrahim Rizvi Department of Biochemistry University of Allahabad Allahabad Uttar Pradesh India

Sy Saeed Department of Psychiatry and Behavioral Medicine Brody School of Medicine at East Carolina University Greenville NC USA

Fabiaacuten Sanchis‐Gomar Department of Physiology School of Medicine University of Valencia Valencia Spain Fundacioacuten del Hospital Cliacutenico Universitario Valencia (FIHCUV‐INCLIVA) Valencia Spain

Estela Santos‐Alves Research Centre in Physical Activity Health and Leisure (CIAFEL) Faculty of Sport University of Porto Porto Portugal

S Manjunatha Endocrine Research Unit Mayo Clinic College of Medicine Rochester MN USA

Maria Fiatarone Singh Exercise Health and Performance Faculty Research Group Sydney Medical School The University of Sydney Lid-combe New South Wales Australia Hebrew SeniorLife Boston MA USA Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University Boston MA USA

Patsri Srisuwan Outpatient and Family Medicine Department Phramongkutklao Hospital and College of Medicine Bangkok Thailand

Richard J Stevenson Department of Psychology Macquarie University Sydney New South Wales Australia

Mark R Zielinski Department of Psychiatry Harvard Medical School and Veterans Affairs Boston Healthcare System West Roxbury MA USA

FoREWoRD

the brain is a plastic organ that is continuously changing and adapting to its environment because of this natural capacity for plasticity there has been an increasing interest from both scientific and public policy groups to attempt to leverage brain plasticity to prevent or treat neurological and psy-chiatric conditions From this perspective there have emerged three categories of treatments that attempt to take advantage of brain plasticity First there are traditional pharmaceutical treatments that try to manipulate the molecular milieu of the brain through medication thereby influencing the prevalence and trajectory of brain disorders unfortunately effective pharmaceutical treatments with minimal side effects and high compliance rates have remained elusive for many disorders of the brain thus in contrast to pharmaceutical approaches the other two approaches are nonphar-maceutical in nature and include (1) behavioral therapies (eg cognitive behavioral therapy) and (2) lifestyle changes (eg exercise habits) these two approaches are often referred to as ldquononpharmaceuti-calrdquo in the sense that they are not medication based However the term ldquononpharmaceuticalrdquo should not be confused with ldquononpharmacologicalrdquo indeed behavioral and lifestyle treatments are methods of manipulating the endogenous pharmacology of the brain

over the past decade there has been an explosion of scientific interest in ldquononpharmaceuticalrdquo approaches to brain plasticity especially those

approaches that include lifestyles (eg exercise habits) this body of work emerges within the context of a well‐established research demonstrating the impact of health behaviors on the function and integrity of visceral organs and physical health Amazingly it has been only relatively recently that the brain and its functions (eg cognition) have been considered as being closely linked to health behaviors such as physical activity and dietary habits indeed as the chapters in this book discuss the brain and its functions are highly susceptible to the same types of decay and dysfunction from engagement in unhealthy lifestyles as the rest of the body Fortunately massive amounts of research have now clearly demonstrated the importance of dietary and exercise habits with cognitive and brain function or diseases and suggest that these effects of unhealthy behaviors on the brain are modifiable For example the work by our group found that engagement in moderate‐intensity exercise several days a week for 1 year was sufficient for increasing the size of the hippocampus in a sample of cognitively healthy but sedentary elderly [1] interestingly the change in hippocampal volume was correlated with changes in spatial memory performance for the exercise group and not for the control group indicating that the changes in hippocampal volume were not a mean-ingless by‐product of greater exercise participation but rather that they had significant implications for cognitive function such findings indicate not only that the brain remains plastic but also that

xvi Foreword

engagement in exercise has the capability of modi-fying the structural integrity of the brain Many other studies have also reported similar effects of exercise physical activity and fitness on biomarkers brain health and cognitive function

As will be described throughout this book despite some consensus on the importance of exercise and dietary lifestyles for brain function there remains debate about the mechanisms the dosendashresponse and the extent to which these life-style choices are effective for both primary and secondary prevention of disease and long‐term treatment for the attenuation of cognitive or brain losses it will be necessary for well‐controlled randomized trials and longitudinal studies with larger sample sizes to more conclusively link these lifestyle approaches to improvements in cognitive and brain health Yet despite this need there is a growing consensus that dietary and exercise habits are important modifiable behaviors that directly influence cognitive and brain health throughout the lifespan the focus of this book titled Diet and

Exercise in Cognitive Function and Neurological Diseases addresses these topics and presents a timely and comprehensive review from world experts in neuroscience epidemiology neurology cognitive psychology nutrition genetics and exercise science this book will provide an excel-lent resource for students and researchers and serve as a guide for the development of future research projects and for the integration of health behaviors into clinical practice and public policies that strive to enhance cognitive and brain health

REFERENCE

1 erickson Ki et al exercise training increases size of hippocampus and improves memory Proc Natl Acad Sci U S A 2011 108(7) pp 3017ndash22

Kirk i erickson

Department of Psychology University of Pittsburgh

Pittsburgh PA USA

this is my warm welcome to the world of ldquodiet and exercise in cognitive function and neurological diseasesrdquo eating food and exercise are two fundamental activities in animal species they use three macronutrients for energy including carbohy-drates proteins and fatty acids Although the world Health organization (wHo) prioritizes ldquostopping hungerrdquo as a highest priority overnu-trition clearly is a concern on numerous health problems in the united states our body does not have positive mechanisms to remove overnu-trition which is why exercise has been a major intervention in order to reduce energy that is taken too much

the central nervous system (Cns) is a hungry tissue for energy it needs energy for a wide variety of functions and therefore when metabolic path-ways are altered Cns is in a big trouble in diabetes high glucose in the blood is characteristic due to deficits in insulin or insulin pathways the Alzheimerrsquos disease (Ad) which is a major cause of dementia shares characteristics of diabetes in the brainmdashit has been proposed to be classified as ldquotype 3 diabetesrdquo in Ad some neurons cannot take glucose inside as well as cannot use the secondary energy source neither with abundant glucose the body thinks why we should use the second energy source ketone bodies (and it does not use ketone

bodies) to turn the situation better glucose levels should be lower so that the neurons start to use ketone bodies

in Ad and some neurological diseases reducing glucose seems to be an effective strategy to provide the secondary energy to the neurons Low‐carbohydrate (low‐carb) diet has a direct effect on reducing glucose and importantly reducing insulin we now know reducing iGF‐1insulin signal can extend lifespan in a wide variety of species from worms to flies and to mammals Low‐carb diet may have a beneficial effect on extending lifespan

Ketogenic diet uses low carb to reduce glucose and high lipids to provide ketone bodies which is a promising treatment in the future Ketogenic diet has originally been used for the treatment of a neurological disease epilepsy However it needs a caution about complex effects of lipids some of which have negative effects on patients with cardiovascular diseases it is essential to shift the diet strategy to the lipids that have neutral or beneficial effects on the health Applications of the diet to diabetes and Ad have been considered

this book will provide a nicely blended over-view of diet and exercise it has chapters describing various types of diet including among

FoREWoRD

xviii Foreword

others ketogenic diet Mediterranean diet and n‐3 (omega‐3) diet other chapters describe a wide variety of benefits on exercise some toxic nutritional metabolites are also getting attention including homocysteine which is linked to methi-onine metabolism Methionine together with folic acidvitamin b12 has been implicated to play a role in normal aging

i would like to thank the editors for the opportunity to write Foreword of this exciting book

shin Murakami Phd

Department of Basic Sciences College of Osteopathic Medicine

Touro University California Vallejo CA USA

Diet and exercise play an important role in maintaining good cognitive function and longevity Macro‐ and micronutrients not only provide energy and building material to the body but also have ability to prevent and protect against age‐related neurological disor-ders Exercise initiates the maintenance of good cardiorespiratory cardiovascular cerebrovascular and muscular fitness by increasing energy con-sumption improving insulin sensitivity increasing blood flow increasing the expression of brain‐derived neurotrophic factor and reducing inflammation Western diet which is enriched in refined carbohy-drates (simple sugars) partially hydrogenated oils (peanut corn soybean and canola) and proteins of animal origin (enriched in corn‐based livestock) is high in salt and low in fiber At present in Western diet the ratio of arachidonic acid (ARA) to docosa-hexaenoic acid (DHA) is about 201 By contrast the Paleolithic diet (stone‐age diet) on which our forefathers lived and survived throughout their his-tory contained high amounts of fresh fruits green vegetables lean meats fish seeds piths and barks with ARA to DHA ratio of 11 Long‐term con-sumption of Western diet produces detrimental effect on health not only by inducing an increase in systemic and brain inflammation and oxidative stress through the stimulation of insulin‐like growth factor 1 (IGF‐1) and Toll‐like receptors and generation of high levels of ARA‐derived lipid mediators but also by mediating abnormalities in mitochondrial function along with the induction of

insulin resistance and leptin resistance in visceral organs and the brain The onset and induction of oxidative stress neuroinflammation and abnormal-ities in mitochondrial function are closely associated with impairments in frontal limbic and hippocampal systems leading to changes in learning memory cognition and hedonics In visceral tissues oxidative stress and inflammation along with genetic and environmental factors promote obesity diabetes metabolic syndrome heart disease and cancer These pathological conditions are risk factors for neurological disorders (stroke AD and depression) Thus incidences of neurological disorders are two‐ to threefold higher in patients with type 2 diabetes metabolic syndrome and cardiovascular diseases compared to normal subjects of the same age

The Mediterranean diet which is enriched in fruits vegetables garlic legumes and unrefined cereals and has moderate amount of fish and high amount of olive oil along with modest intake of red wine produces anti‐inflammatory antioxidant and antidiabetic effects leading to cardio‐ and neuroprotection in heart disease and neurological disorders

Exercise initiates the maintenance of good car-diorespiratory cardiovascular cerebrovascular and muscular fitness by preventing metabolic imbalance increasing energy consumption improving insulin sensitivity increasing blood flow elevating levels of brain‐derived neurotrophic factor reducing inflammation and enhancing learning and memory

PREFACE

xx PREFACE

Good nutrition daily exercise and adequate sleep are the foundations for maintaining optimal health

Information on diet and exercise is scattered throughout the literature in the form of original papers reviews and some books These books describe the effects of diet and exercise on visceral organs The purpose of this edited book is to pro-vide readers with a comprehensive and cutting‐edge information on the effects of diet and exercise on cognitive function and age‐related visceral and brain diseases in a manner which is useful not only to students and teachers but also to researchers dietitians nutritionists exercise physiologists and physicians To the best of our knowledge this edited book will be the first to provide a comprehensive description of signal transduction processes associated with the effects of diet and exercise on the cognitive function

This edited book has 28 chapters Chapters 1ndash9 describe the effects of various diet patterns on metabolic changes in visceral organs and the brain Chapters 10ndash26 provide information on the effects of diet and exercise on cognitive function and age‐related neurological disorders Chapter 27 deals

with the role of salt in the pathogenesis of dementia and stroke Finally Chapter 28 deals with perspective on the current progress that will be important for future studies on the effects of diet and exercise on cognitive function in normal subjects and age‐related neurological disorders

Our contributors have tried to ensure uniformity and mode of presentation simple and we have made sure that the progression of subject matter from one topic to another is logical Each chapter provides an extensive bibliography for readers to consult For the sake of simplicity and uniformity a large number of figures with chemical structures of metabolites along with line diagrams of colored signal transduction pathways are included We hope that our attempt to integrate and consolidate the knowledge on the effects of diet and exercise on cognitive function will initiate more studies on molecular mechanisms that link among diet and exercise with cognitive function in normal subjects and patients with age‐related neu-rological disorders

Tahira Farooqui Akhlaq A Farooqui

We thank all the authors of this book who shared their expertise by contributing chapters of a high standard thus making our editorial task much easier We are grateful to Justin Jeffryes Editorial Director at Wiley‐Blackwell for his cooperation and patience during this process We are also

thankful to Stephanie Dollan Senior Editorial Assistant at Wiley‐Blackwell for her professional handling of the manuscript

Tahira FarooquiAkhlaq A Farooqui

ACKNOWLEDGMENTS

Diet and Exercise in Cognitive Function and Neurological Diseases First Edition Edited by Tahira Farooqui and Akhlaq A Farooqui copy 2015 John Wiley amp Sons Inc Published 2015 by John Wiley amp Sons Inc

11 INTRODUCTION

Nutritionndashgene interactions play a pivotal role in cognitive function and neurological disease throughout life Nutrition is one of many environ-mental factors that profoundly alter the phenotypic expression of a given genotype with major impli-cations for development metabolism health and disease [1ndash4] These effects are mediated by changes in expression of multiple genes and can involve epigenetic mechanisms nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence Responses to nutrition are in turn affected by individual genetic variability The effects of nutrition on gene expression are exerted throughout the life cycle with prenatal and early postnatal life being especially critical periods for optimal development Changes in gene expression may be dynamic and short term stable and long term and even heritable between cell divisions and across generations

This review focuses on the following key topics First a short overview is provided on the role of nutrition in cognitive neuroscience Second mecha-nisms underlying nutritionndashgene interactions are discussed especially in relation to the roles of epige-netics and genetic variability in neuroscience

Third attention is focused on the importance of environment and epigenetics in neurological health and disease Finally the role of early nutrition in brain development and later neurological disease is addressed Overall this review highlights the criti-cal importance of nutritionndashgene interactions to optimal neurological function and prevention and treatment of multiple neurological disorders

12 NUTRITION AND COGNITIVE NEUROSCIENCE

The role of nutrition in cognitive neuroscience is highly complex because as with all aspects of nutrition it is multifactorial It is not concerned simply with the impact of a single chemical on the brain but with numerous interactions between multiple nutrients metabolites food and other environmental and genetic factors Nevertheless considerable evidence now links many aspects of nutrition with cognition mental health and well‐being neurological dysfunction and disease [1ndash9] Protective roles are suggested for the Mediterranean diet optimal energy status fish fruits vegetables polyphenols omega‐3 polyunsaturated fatty acids iron zinc copper and numerous vitamins

NUTRITION GENES AND NEUROSCIENCE IMPLICATIONS FOR DEVELOPMENT HEALTH AND DISEASE

Margaret Joy DaunceyWolfson College University of Cambridge Cambridge UK

1

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

FoREWoRD

the brain is a plastic organ that is continuously changing and adapting to its environment because of this natural capacity for plasticity there has been an increasing interest from both scientific and public policy groups to attempt to leverage brain plasticity to prevent or treat neurological and psy-chiatric conditions From this perspective there have emerged three categories of treatments that attempt to take advantage of brain plasticity First there are traditional pharmaceutical treatments that try to manipulate the molecular milieu of the brain through medication thereby influencing the prevalence and trajectory of brain disorders unfortunately effective pharmaceutical treatments with minimal side effects and high compliance rates have remained elusive for many disorders of the brain thus in contrast to pharmaceutical approaches the other two approaches are nonphar-maceutical in nature and include (1) behavioral therapies (eg cognitive behavioral therapy) and (2) lifestyle changes (eg exercise habits) these two approaches are often referred to as ldquononpharmaceuti-calrdquo in the sense that they are not medication based However the term ldquononpharmaceuticalrdquo should not be confused with ldquononpharmacologicalrdquo indeed behavioral and lifestyle treatments are methods of manipulating the endogenous pharmacology of the brain

over the past decade there has been an explosion of scientific interest in ldquononpharmaceuticalrdquo approaches to brain plasticity especially those

approaches that include lifestyles (eg exercise habits) this body of work emerges within the context of a well‐established research demonstrating the impact of health behaviors on the function and integrity of visceral organs and physical health Amazingly it has been only relatively recently that the brain and its functions (eg cognition) have been considered as being closely linked to health behaviors such as physical activity and dietary habits indeed as the chapters in this book discuss the brain and its functions are highly susceptible to the same types of decay and dysfunction from engagement in unhealthy lifestyles as the rest of the body Fortunately massive amounts of research have now clearly demonstrated the importance of dietary and exercise habits with cognitive and brain function or diseases and suggest that these effects of unhealthy behaviors on the brain are modifiable For example the work by our group found that engagement in moderate‐intensity exercise several days a week for 1 year was sufficient for increasing the size of the hippocampus in a sample of cognitively healthy but sedentary elderly [1] interestingly the change in hippocampal volume was correlated with changes in spatial memory performance for the exercise group and not for the control group indicating that the changes in hippocampal volume were not a mean-ingless by‐product of greater exercise participation but rather that they had significant implications for cognitive function such findings indicate not only that the brain remains plastic but also that

xvi Foreword

engagement in exercise has the capability of modi-fying the structural integrity of the brain Many other studies have also reported similar effects of exercise physical activity and fitness on biomarkers brain health and cognitive function

As will be described throughout this book despite some consensus on the importance of exercise and dietary lifestyles for brain function there remains debate about the mechanisms the dosendashresponse and the extent to which these life-style choices are effective for both primary and secondary prevention of disease and long‐term treatment for the attenuation of cognitive or brain losses it will be necessary for well‐controlled randomized trials and longitudinal studies with larger sample sizes to more conclusively link these lifestyle approaches to improvements in cognitive and brain health Yet despite this need there is a growing consensus that dietary and exercise habits are important modifiable behaviors that directly influence cognitive and brain health throughout the lifespan the focus of this book titled Diet and

Exercise in Cognitive Function and Neurological Diseases addresses these topics and presents a timely and comprehensive review from world experts in neuroscience epidemiology neurology cognitive psychology nutrition genetics and exercise science this book will provide an excel-lent resource for students and researchers and serve as a guide for the development of future research projects and for the integration of health behaviors into clinical practice and public policies that strive to enhance cognitive and brain health

REFERENCE

1 erickson Ki et al exercise training increases size of hippocampus and improves memory Proc Natl Acad Sci U S A 2011 108(7) pp 3017ndash22

Kirk i erickson

Department of Psychology University of Pittsburgh

Pittsburgh PA USA

this is my warm welcome to the world of ldquodiet and exercise in cognitive function and neurological diseasesrdquo eating food and exercise are two fundamental activities in animal species they use three macronutrients for energy including carbohy-drates proteins and fatty acids Although the world Health organization (wHo) prioritizes ldquostopping hungerrdquo as a highest priority overnu-trition clearly is a concern on numerous health problems in the united states our body does not have positive mechanisms to remove overnu-trition which is why exercise has been a major intervention in order to reduce energy that is taken too much

the central nervous system (Cns) is a hungry tissue for energy it needs energy for a wide variety of functions and therefore when metabolic path-ways are altered Cns is in a big trouble in diabetes high glucose in the blood is characteristic due to deficits in insulin or insulin pathways the Alzheimerrsquos disease (Ad) which is a major cause of dementia shares characteristics of diabetes in the brainmdashit has been proposed to be classified as ldquotype 3 diabetesrdquo in Ad some neurons cannot take glucose inside as well as cannot use the secondary energy source neither with abundant glucose the body thinks why we should use the second energy source ketone bodies (and it does not use ketone

bodies) to turn the situation better glucose levels should be lower so that the neurons start to use ketone bodies

in Ad and some neurological diseases reducing glucose seems to be an effective strategy to provide the secondary energy to the neurons Low‐carbohydrate (low‐carb) diet has a direct effect on reducing glucose and importantly reducing insulin we now know reducing iGF‐1insulin signal can extend lifespan in a wide variety of species from worms to flies and to mammals Low‐carb diet may have a beneficial effect on extending lifespan

Ketogenic diet uses low carb to reduce glucose and high lipids to provide ketone bodies which is a promising treatment in the future Ketogenic diet has originally been used for the treatment of a neurological disease epilepsy However it needs a caution about complex effects of lipids some of which have negative effects on patients with cardiovascular diseases it is essential to shift the diet strategy to the lipids that have neutral or beneficial effects on the health Applications of the diet to diabetes and Ad have been considered

this book will provide a nicely blended over-view of diet and exercise it has chapters describing various types of diet including among

FoREWoRD

xviii Foreword

others ketogenic diet Mediterranean diet and n‐3 (omega‐3) diet other chapters describe a wide variety of benefits on exercise some toxic nutritional metabolites are also getting attention including homocysteine which is linked to methi-onine metabolism Methionine together with folic acidvitamin b12 has been implicated to play a role in normal aging

i would like to thank the editors for the opportunity to write Foreword of this exciting book

shin Murakami Phd

Department of Basic Sciences College of Osteopathic Medicine

Touro University California Vallejo CA USA

Diet and exercise play an important role in maintaining good cognitive function and longevity Macro‐ and micronutrients not only provide energy and building material to the body but also have ability to prevent and protect against age‐related neurological disor-ders Exercise initiates the maintenance of good cardiorespiratory cardiovascular cerebrovascular and muscular fitness by increasing energy con-sumption improving insulin sensitivity increasing blood flow increasing the expression of brain‐derived neurotrophic factor and reducing inflammation Western diet which is enriched in refined carbohy-drates (simple sugars) partially hydrogenated oils (peanut corn soybean and canola) and proteins of animal origin (enriched in corn‐based livestock) is high in salt and low in fiber At present in Western diet the ratio of arachidonic acid (ARA) to docosa-hexaenoic acid (DHA) is about 201 By contrast the Paleolithic diet (stone‐age diet) on which our forefathers lived and survived throughout their his-tory contained high amounts of fresh fruits green vegetables lean meats fish seeds piths and barks with ARA to DHA ratio of 11 Long‐term con-sumption of Western diet produces detrimental effect on health not only by inducing an increase in systemic and brain inflammation and oxidative stress through the stimulation of insulin‐like growth factor 1 (IGF‐1) and Toll‐like receptors and generation of high levels of ARA‐derived lipid mediators but also by mediating abnormalities in mitochondrial function along with the induction of

insulin resistance and leptin resistance in visceral organs and the brain The onset and induction of oxidative stress neuroinflammation and abnormal-ities in mitochondrial function are closely associated with impairments in frontal limbic and hippocampal systems leading to changes in learning memory cognition and hedonics In visceral tissues oxidative stress and inflammation along with genetic and environmental factors promote obesity diabetes metabolic syndrome heart disease and cancer These pathological conditions are risk factors for neurological disorders (stroke AD and depression) Thus incidences of neurological disorders are two‐ to threefold higher in patients with type 2 diabetes metabolic syndrome and cardiovascular diseases compared to normal subjects of the same age

The Mediterranean diet which is enriched in fruits vegetables garlic legumes and unrefined cereals and has moderate amount of fish and high amount of olive oil along with modest intake of red wine produces anti‐inflammatory antioxidant and antidiabetic effects leading to cardio‐ and neuroprotection in heart disease and neurological disorders

Exercise initiates the maintenance of good car-diorespiratory cardiovascular cerebrovascular and muscular fitness by preventing metabolic imbalance increasing energy consumption improving insulin sensitivity increasing blood flow elevating levels of brain‐derived neurotrophic factor reducing inflammation and enhancing learning and memory

PREFACE

xx PREFACE

Good nutrition daily exercise and adequate sleep are the foundations for maintaining optimal health

Information on diet and exercise is scattered throughout the literature in the form of original papers reviews and some books These books describe the effects of diet and exercise on visceral organs The purpose of this edited book is to pro-vide readers with a comprehensive and cutting‐edge information on the effects of diet and exercise on cognitive function and age‐related visceral and brain diseases in a manner which is useful not only to students and teachers but also to researchers dietitians nutritionists exercise physiologists and physicians To the best of our knowledge this edited book will be the first to provide a comprehensive description of signal transduction processes associated with the effects of diet and exercise on the cognitive function

This edited book has 28 chapters Chapters 1ndash9 describe the effects of various diet patterns on metabolic changes in visceral organs and the brain Chapters 10ndash26 provide information on the effects of diet and exercise on cognitive function and age‐related neurological disorders Chapter 27 deals

with the role of salt in the pathogenesis of dementia and stroke Finally Chapter 28 deals with perspective on the current progress that will be important for future studies on the effects of diet and exercise on cognitive function in normal subjects and age‐related neurological disorders

Our contributors have tried to ensure uniformity and mode of presentation simple and we have made sure that the progression of subject matter from one topic to another is logical Each chapter provides an extensive bibliography for readers to consult For the sake of simplicity and uniformity a large number of figures with chemical structures of metabolites along with line diagrams of colored signal transduction pathways are included We hope that our attempt to integrate and consolidate the knowledge on the effects of diet and exercise on cognitive function will initiate more studies on molecular mechanisms that link among diet and exercise with cognitive function in normal subjects and patients with age‐related neu-rological disorders

Tahira Farooqui Akhlaq A Farooqui

We thank all the authors of this book who shared their expertise by contributing chapters of a high standard thus making our editorial task much easier We are grateful to Justin Jeffryes Editorial Director at Wiley‐Blackwell for his cooperation and patience during this process We are also

thankful to Stephanie Dollan Senior Editorial Assistant at Wiley‐Blackwell for her professional handling of the manuscript

Tahira FarooquiAkhlaq A Farooqui

ACKNOWLEDGMENTS

Diet and Exercise in Cognitive Function and Neurological Diseases First Edition Edited by Tahira Farooqui and Akhlaq A Farooqui copy 2015 John Wiley amp Sons Inc Published 2015 by John Wiley amp Sons Inc

11 INTRODUCTION

Nutritionndashgene interactions play a pivotal role in cognitive function and neurological disease throughout life Nutrition is one of many environ-mental factors that profoundly alter the phenotypic expression of a given genotype with major impli-cations for development metabolism health and disease [1ndash4] These effects are mediated by changes in expression of multiple genes and can involve epigenetic mechanisms nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence Responses to nutrition are in turn affected by individual genetic variability The effects of nutrition on gene expression are exerted throughout the life cycle with prenatal and early postnatal life being especially critical periods for optimal development Changes in gene expression may be dynamic and short term stable and long term and even heritable between cell divisions and across generations

This review focuses on the following key topics First a short overview is provided on the role of nutrition in cognitive neuroscience Second mecha-nisms underlying nutritionndashgene interactions are discussed especially in relation to the roles of epige-netics and genetic variability in neuroscience

Third attention is focused on the importance of environment and epigenetics in neurological health and disease Finally the role of early nutrition in brain development and later neurological disease is addressed Overall this review highlights the criti-cal importance of nutritionndashgene interactions to optimal neurological function and prevention and treatment of multiple neurological disorders

12 NUTRITION AND COGNITIVE NEUROSCIENCE

The role of nutrition in cognitive neuroscience is highly complex because as with all aspects of nutrition it is multifactorial It is not concerned simply with the impact of a single chemical on the brain but with numerous interactions between multiple nutrients metabolites food and other environmental and genetic factors Nevertheless considerable evidence now links many aspects of nutrition with cognition mental health and well‐being neurological dysfunction and disease [1ndash9] Protective roles are suggested for the Mediterranean diet optimal energy status fish fruits vegetables polyphenols omega‐3 polyunsaturated fatty acids iron zinc copper and numerous vitamins

NUTRITION GENES AND NEUROSCIENCE IMPLICATIONS FOR DEVELOPMENT HEALTH AND DISEASE

Margaret Joy DaunceyWolfson College University of Cambridge Cambridge UK

1

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

xvi Foreword

engagement in exercise has the capability of modi-fying the structural integrity of the brain Many other studies have also reported similar effects of exercise physical activity and fitness on biomarkers brain health and cognitive function

As will be described throughout this book despite some consensus on the importance of exercise and dietary lifestyles for brain function there remains debate about the mechanisms the dosendashresponse and the extent to which these life-style choices are effective for both primary and secondary prevention of disease and long‐term treatment for the attenuation of cognitive or brain losses it will be necessary for well‐controlled randomized trials and longitudinal studies with larger sample sizes to more conclusively link these lifestyle approaches to improvements in cognitive and brain health Yet despite this need there is a growing consensus that dietary and exercise habits are important modifiable behaviors that directly influence cognitive and brain health throughout the lifespan the focus of this book titled Diet and

Exercise in Cognitive Function and Neurological Diseases addresses these topics and presents a timely and comprehensive review from world experts in neuroscience epidemiology neurology cognitive psychology nutrition genetics and exercise science this book will provide an excel-lent resource for students and researchers and serve as a guide for the development of future research projects and for the integration of health behaviors into clinical practice and public policies that strive to enhance cognitive and brain health

REFERENCE

1 erickson Ki et al exercise training increases size of hippocampus and improves memory Proc Natl Acad Sci U S A 2011 108(7) pp 3017ndash22

Kirk i erickson

Department of Psychology University of Pittsburgh

Pittsburgh PA USA

this is my warm welcome to the world of ldquodiet and exercise in cognitive function and neurological diseasesrdquo eating food and exercise are two fundamental activities in animal species they use three macronutrients for energy including carbohy-drates proteins and fatty acids Although the world Health organization (wHo) prioritizes ldquostopping hungerrdquo as a highest priority overnu-trition clearly is a concern on numerous health problems in the united states our body does not have positive mechanisms to remove overnu-trition which is why exercise has been a major intervention in order to reduce energy that is taken too much

the central nervous system (Cns) is a hungry tissue for energy it needs energy for a wide variety of functions and therefore when metabolic path-ways are altered Cns is in a big trouble in diabetes high glucose in the blood is characteristic due to deficits in insulin or insulin pathways the Alzheimerrsquos disease (Ad) which is a major cause of dementia shares characteristics of diabetes in the brainmdashit has been proposed to be classified as ldquotype 3 diabetesrdquo in Ad some neurons cannot take glucose inside as well as cannot use the secondary energy source neither with abundant glucose the body thinks why we should use the second energy source ketone bodies (and it does not use ketone

bodies) to turn the situation better glucose levels should be lower so that the neurons start to use ketone bodies

in Ad and some neurological diseases reducing glucose seems to be an effective strategy to provide the secondary energy to the neurons Low‐carbohydrate (low‐carb) diet has a direct effect on reducing glucose and importantly reducing insulin we now know reducing iGF‐1insulin signal can extend lifespan in a wide variety of species from worms to flies and to mammals Low‐carb diet may have a beneficial effect on extending lifespan

Ketogenic diet uses low carb to reduce glucose and high lipids to provide ketone bodies which is a promising treatment in the future Ketogenic diet has originally been used for the treatment of a neurological disease epilepsy However it needs a caution about complex effects of lipids some of which have negative effects on patients with cardiovascular diseases it is essential to shift the diet strategy to the lipids that have neutral or beneficial effects on the health Applications of the diet to diabetes and Ad have been considered

this book will provide a nicely blended over-view of diet and exercise it has chapters describing various types of diet including among

FoREWoRD

xviii Foreword

others ketogenic diet Mediterranean diet and n‐3 (omega‐3) diet other chapters describe a wide variety of benefits on exercise some toxic nutritional metabolites are also getting attention including homocysteine which is linked to methi-onine metabolism Methionine together with folic acidvitamin b12 has been implicated to play a role in normal aging

i would like to thank the editors for the opportunity to write Foreword of this exciting book

shin Murakami Phd

Department of Basic Sciences College of Osteopathic Medicine

Touro University California Vallejo CA USA

Diet and exercise play an important role in maintaining good cognitive function and longevity Macro‐ and micronutrients not only provide energy and building material to the body but also have ability to prevent and protect against age‐related neurological disor-ders Exercise initiates the maintenance of good cardiorespiratory cardiovascular cerebrovascular and muscular fitness by increasing energy con-sumption improving insulin sensitivity increasing blood flow increasing the expression of brain‐derived neurotrophic factor and reducing inflammation Western diet which is enriched in refined carbohy-drates (simple sugars) partially hydrogenated oils (peanut corn soybean and canola) and proteins of animal origin (enriched in corn‐based livestock) is high in salt and low in fiber At present in Western diet the ratio of arachidonic acid (ARA) to docosa-hexaenoic acid (DHA) is about 201 By contrast the Paleolithic diet (stone‐age diet) on which our forefathers lived and survived throughout their his-tory contained high amounts of fresh fruits green vegetables lean meats fish seeds piths and barks with ARA to DHA ratio of 11 Long‐term con-sumption of Western diet produces detrimental effect on health not only by inducing an increase in systemic and brain inflammation and oxidative stress through the stimulation of insulin‐like growth factor 1 (IGF‐1) and Toll‐like receptors and generation of high levels of ARA‐derived lipid mediators but also by mediating abnormalities in mitochondrial function along with the induction of

insulin resistance and leptin resistance in visceral organs and the brain The onset and induction of oxidative stress neuroinflammation and abnormal-ities in mitochondrial function are closely associated with impairments in frontal limbic and hippocampal systems leading to changes in learning memory cognition and hedonics In visceral tissues oxidative stress and inflammation along with genetic and environmental factors promote obesity diabetes metabolic syndrome heart disease and cancer These pathological conditions are risk factors for neurological disorders (stroke AD and depression) Thus incidences of neurological disorders are two‐ to threefold higher in patients with type 2 diabetes metabolic syndrome and cardiovascular diseases compared to normal subjects of the same age

The Mediterranean diet which is enriched in fruits vegetables garlic legumes and unrefined cereals and has moderate amount of fish and high amount of olive oil along with modest intake of red wine produces anti‐inflammatory antioxidant and antidiabetic effects leading to cardio‐ and neuroprotection in heart disease and neurological disorders

Exercise initiates the maintenance of good car-diorespiratory cardiovascular cerebrovascular and muscular fitness by preventing metabolic imbalance increasing energy consumption improving insulin sensitivity increasing blood flow elevating levels of brain‐derived neurotrophic factor reducing inflammation and enhancing learning and memory

PREFACE

xx PREFACE

Good nutrition daily exercise and adequate sleep are the foundations for maintaining optimal health

Information on diet and exercise is scattered throughout the literature in the form of original papers reviews and some books These books describe the effects of diet and exercise on visceral organs The purpose of this edited book is to pro-vide readers with a comprehensive and cutting‐edge information on the effects of diet and exercise on cognitive function and age‐related visceral and brain diseases in a manner which is useful not only to students and teachers but also to researchers dietitians nutritionists exercise physiologists and physicians To the best of our knowledge this edited book will be the first to provide a comprehensive description of signal transduction processes associated with the effects of diet and exercise on the cognitive function

This edited book has 28 chapters Chapters 1ndash9 describe the effects of various diet patterns on metabolic changes in visceral organs and the brain Chapters 10ndash26 provide information on the effects of diet and exercise on cognitive function and age‐related neurological disorders Chapter 27 deals

with the role of salt in the pathogenesis of dementia and stroke Finally Chapter 28 deals with perspective on the current progress that will be important for future studies on the effects of diet and exercise on cognitive function in normal subjects and age‐related neurological disorders

Our contributors have tried to ensure uniformity and mode of presentation simple and we have made sure that the progression of subject matter from one topic to another is logical Each chapter provides an extensive bibliography for readers to consult For the sake of simplicity and uniformity a large number of figures with chemical structures of metabolites along with line diagrams of colored signal transduction pathways are included We hope that our attempt to integrate and consolidate the knowledge on the effects of diet and exercise on cognitive function will initiate more studies on molecular mechanisms that link among diet and exercise with cognitive function in normal subjects and patients with age‐related neu-rological disorders

Tahira Farooqui Akhlaq A Farooqui

We thank all the authors of this book who shared their expertise by contributing chapters of a high standard thus making our editorial task much easier We are grateful to Justin Jeffryes Editorial Director at Wiley‐Blackwell for his cooperation and patience during this process We are also

thankful to Stephanie Dollan Senior Editorial Assistant at Wiley‐Blackwell for her professional handling of the manuscript

Tahira FarooquiAkhlaq A Farooqui

ACKNOWLEDGMENTS

Diet and Exercise in Cognitive Function and Neurological Diseases First Edition Edited by Tahira Farooqui and Akhlaq A Farooqui copy 2015 John Wiley amp Sons Inc Published 2015 by John Wiley amp Sons Inc

11 INTRODUCTION

Nutritionndashgene interactions play a pivotal role in cognitive function and neurological disease throughout life Nutrition is one of many environ-mental factors that profoundly alter the phenotypic expression of a given genotype with major impli-cations for development metabolism health and disease [1ndash4] These effects are mediated by changes in expression of multiple genes and can involve epigenetic mechanisms nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence Responses to nutrition are in turn affected by individual genetic variability The effects of nutrition on gene expression are exerted throughout the life cycle with prenatal and early postnatal life being especially critical periods for optimal development Changes in gene expression may be dynamic and short term stable and long term and even heritable between cell divisions and across generations

This review focuses on the following key topics First a short overview is provided on the role of nutrition in cognitive neuroscience Second mecha-nisms underlying nutritionndashgene interactions are discussed especially in relation to the roles of epige-netics and genetic variability in neuroscience

Third attention is focused on the importance of environment and epigenetics in neurological health and disease Finally the role of early nutrition in brain development and later neurological disease is addressed Overall this review highlights the criti-cal importance of nutritionndashgene interactions to optimal neurological function and prevention and treatment of multiple neurological disorders

12 NUTRITION AND COGNITIVE NEUROSCIENCE

The role of nutrition in cognitive neuroscience is highly complex because as with all aspects of nutrition it is multifactorial It is not concerned simply with the impact of a single chemical on the brain but with numerous interactions between multiple nutrients metabolites food and other environmental and genetic factors Nevertheless considerable evidence now links many aspects of nutrition with cognition mental health and well‐being neurological dysfunction and disease [1ndash9] Protective roles are suggested for the Mediterranean diet optimal energy status fish fruits vegetables polyphenols omega‐3 polyunsaturated fatty acids iron zinc copper and numerous vitamins

NUTRITION GENES AND NEUROSCIENCE IMPLICATIONS FOR DEVELOPMENT HEALTH AND DISEASE

Margaret Joy DaunceyWolfson College University of Cambridge Cambridge UK

1

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

this is my warm welcome to the world of ldquodiet and exercise in cognitive function and neurological diseasesrdquo eating food and exercise are two fundamental activities in animal species they use three macronutrients for energy including carbohy-drates proteins and fatty acids Although the world Health organization (wHo) prioritizes ldquostopping hungerrdquo as a highest priority overnu-trition clearly is a concern on numerous health problems in the united states our body does not have positive mechanisms to remove overnu-trition which is why exercise has been a major intervention in order to reduce energy that is taken too much

the central nervous system (Cns) is a hungry tissue for energy it needs energy for a wide variety of functions and therefore when metabolic path-ways are altered Cns is in a big trouble in diabetes high glucose in the blood is characteristic due to deficits in insulin or insulin pathways the Alzheimerrsquos disease (Ad) which is a major cause of dementia shares characteristics of diabetes in the brainmdashit has been proposed to be classified as ldquotype 3 diabetesrdquo in Ad some neurons cannot take glucose inside as well as cannot use the secondary energy source neither with abundant glucose the body thinks why we should use the second energy source ketone bodies (and it does not use ketone

bodies) to turn the situation better glucose levels should be lower so that the neurons start to use ketone bodies

in Ad and some neurological diseases reducing glucose seems to be an effective strategy to provide the secondary energy to the neurons Low‐carbohydrate (low‐carb) diet has a direct effect on reducing glucose and importantly reducing insulin we now know reducing iGF‐1insulin signal can extend lifespan in a wide variety of species from worms to flies and to mammals Low‐carb diet may have a beneficial effect on extending lifespan

Ketogenic diet uses low carb to reduce glucose and high lipids to provide ketone bodies which is a promising treatment in the future Ketogenic diet has originally been used for the treatment of a neurological disease epilepsy However it needs a caution about complex effects of lipids some of which have negative effects on patients with cardiovascular diseases it is essential to shift the diet strategy to the lipids that have neutral or beneficial effects on the health Applications of the diet to diabetes and Ad have been considered

this book will provide a nicely blended over-view of diet and exercise it has chapters describing various types of diet including among

FoREWoRD

xviii Foreword

others ketogenic diet Mediterranean diet and n‐3 (omega‐3) diet other chapters describe a wide variety of benefits on exercise some toxic nutritional metabolites are also getting attention including homocysteine which is linked to methi-onine metabolism Methionine together with folic acidvitamin b12 has been implicated to play a role in normal aging

i would like to thank the editors for the opportunity to write Foreword of this exciting book

shin Murakami Phd

Department of Basic Sciences College of Osteopathic Medicine

Touro University California Vallejo CA USA

Diet and exercise play an important role in maintaining good cognitive function and longevity Macro‐ and micronutrients not only provide energy and building material to the body but also have ability to prevent and protect against age‐related neurological disor-ders Exercise initiates the maintenance of good cardiorespiratory cardiovascular cerebrovascular and muscular fitness by increasing energy con-sumption improving insulin sensitivity increasing blood flow increasing the expression of brain‐derived neurotrophic factor and reducing inflammation Western diet which is enriched in refined carbohy-drates (simple sugars) partially hydrogenated oils (peanut corn soybean and canola) and proteins of animal origin (enriched in corn‐based livestock) is high in salt and low in fiber At present in Western diet the ratio of arachidonic acid (ARA) to docosa-hexaenoic acid (DHA) is about 201 By contrast the Paleolithic diet (stone‐age diet) on which our forefathers lived and survived throughout their his-tory contained high amounts of fresh fruits green vegetables lean meats fish seeds piths and barks with ARA to DHA ratio of 11 Long‐term con-sumption of Western diet produces detrimental effect on health not only by inducing an increase in systemic and brain inflammation and oxidative stress through the stimulation of insulin‐like growth factor 1 (IGF‐1) and Toll‐like receptors and generation of high levels of ARA‐derived lipid mediators but also by mediating abnormalities in mitochondrial function along with the induction of

insulin resistance and leptin resistance in visceral organs and the brain The onset and induction of oxidative stress neuroinflammation and abnormal-ities in mitochondrial function are closely associated with impairments in frontal limbic and hippocampal systems leading to changes in learning memory cognition and hedonics In visceral tissues oxidative stress and inflammation along with genetic and environmental factors promote obesity diabetes metabolic syndrome heart disease and cancer These pathological conditions are risk factors for neurological disorders (stroke AD and depression) Thus incidences of neurological disorders are two‐ to threefold higher in patients with type 2 diabetes metabolic syndrome and cardiovascular diseases compared to normal subjects of the same age

The Mediterranean diet which is enriched in fruits vegetables garlic legumes and unrefined cereals and has moderate amount of fish and high amount of olive oil along with modest intake of red wine produces anti‐inflammatory antioxidant and antidiabetic effects leading to cardio‐ and neuroprotection in heart disease and neurological disorders

Exercise initiates the maintenance of good car-diorespiratory cardiovascular cerebrovascular and muscular fitness by preventing metabolic imbalance increasing energy consumption improving insulin sensitivity increasing blood flow elevating levels of brain‐derived neurotrophic factor reducing inflammation and enhancing learning and memory

PREFACE

xx PREFACE

Good nutrition daily exercise and adequate sleep are the foundations for maintaining optimal health

Information on diet and exercise is scattered throughout the literature in the form of original papers reviews and some books These books describe the effects of diet and exercise on visceral organs The purpose of this edited book is to pro-vide readers with a comprehensive and cutting‐edge information on the effects of diet and exercise on cognitive function and age‐related visceral and brain diseases in a manner which is useful not only to students and teachers but also to researchers dietitians nutritionists exercise physiologists and physicians To the best of our knowledge this edited book will be the first to provide a comprehensive description of signal transduction processes associated with the effects of diet and exercise on the cognitive function

This edited book has 28 chapters Chapters 1ndash9 describe the effects of various diet patterns on metabolic changes in visceral organs and the brain Chapters 10ndash26 provide information on the effects of diet and exercise on cognitive function and age‐related neurological disorders Chapter 27 deals

with the role of salt in the pathogenesis of dementia and stroke Finally Chapter 28 deals with perspective on the current progress that will be important for future studies on the effects of diet and exercise on cognitive function in normal subjects and age‐related neurological disorders

Our contributors have tried to ensure uniformity and mode of presentation simple and we have made sure that the progression of subject matter from one topic to another is logical Each chapter provides an extensive bibliography for readers to consult For the sake of simplicity and uniformity a large number of figures with chemical structures of metabolites along with line diagrams of colored signal transduction pathways are included We hope that our attempt to integrate and consolidate the knowledge on the effects of diet and exercise on cognitive function will initiate more studies on molecular mechanisms that link among diet and exercise with cognitive function in normal subjects and patients with age‐related neu-rological disorders

Tahira Farooqui Akhlaq A Farooqui

We thank all the authors of this book who shared their expertise by contributing chapters of a high standard thus making our editorial task much easier We are grateful to Justin Jeffryes Editorial Director at Wiley‐Blackwell for his cooperation and patience during this process We are also

thankful to Stephanie Dollan Senior Editorial Assistant at Wiley‐Blackwell for her professional handling of the manuscript

Tahira FarooquiAkhlaq A Farooqui

ACKNOWLEDGMENTS

Diet and Exercise in Cognitive Function and Neurological Diseases First Edition Edited by Tahira Farooqui and Akhlaq A Farooqui copy 2015 John Wiley amp Sons Inc Published 2015 by John Wiley amp Sons Inc

11 INTRODUCTION

Nutritionndashgene interactions play a pivotal role in cognitive function and neurological disease throughout life Nutrition is one of many environ-mental factors that profoundly alter the phenotypic expression of a given genotype with major impli-cations for development metabolism health and disease [1ndash4] These effects are mediated by changes in expression of multiple genes and can involve epigenetic mechanisms nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence Responses to nutrition are in turn affected by individual genetic variability The effects of nutrition on gene expression are exerted throughout the life cycle with prenatal and early postnatal life being especially critical periods for optimal development Changes in gene expression may be dynamic and short term stable and long term and even heritable between cell divisions and across generations

This review focuses on the following key topics First a short overview is provided on the role of nutrition in cognitive neuroscience Second mecha-nisms underlying nutritionndashgene interactions are discussed especially in relation to the roles of epige-netics and genetic variability in neuroscience

Third attention is focused on the importance of environment and epigenetics in neurological health and disease Finally the role of early nutrition in brain development and later neurological disease is addressed Overall this review highlights the criti-cal importance of nutritionndashgene interactions to optimal neurological function and prevention and treatment of multiple neurological disorders

12 NUTRITION AND COGNITIVE NEUROSCIENCE

The role of nutrition in cognitive neuroscience is highly complex because as with all aspects of nutrition it is multifactorial It is not concerned simply with the impact of a single chemical on the brain but with numerous interactions between multiple nutrients metabolites food and other environmental and genetic factors Nevertheless considerable evidence now links many aspects of nutrition with cognition mental health and well‐being neurological dysfunction and disease [1ndash9] Protective roles are suggested for the Mediterranean diet optimal energy status fish fruits vegetables polyphenols omega‐3 polyunsaturated fatty acids iron zinc copper and numerous vitamins

NUTRITION GENES AND NEUROSCIENCE IMPLICATIONS FOR DEVELOPMENT HEALTH AND DISEASE

Margaret Joy DaunceyWolfson College University of Cambridge Cambridge UK

1

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

xviii Foreword

others ketogenic diet Mediterranean diet and n‐3 (omega‐3) diet other chapters describe a wide variety of benefits on exercise some toxic nutritional metabolites are also getting attention including homocysteine which is linked to methi-onine metabolism Methionine together with folic acidvitamin b12 has been implicated to play a role in normal aging

i would like to thank the editors for the opportunity to write Foreword of this exciting book

shin Murakami Phd

Department of Basic Sciences College of Osteopathic Medicine

Touro University California Vallejo CA USA

Diet and exercise play an important role in maintaining good cognitive function and longevity Macro‐ and micronutrients not only provide energy and building material to the body but also have ability to prevent and protect against age‐related neurological disor-ders Exercise initiates the maintenance of good cardiorespiratory cardiovascular cerebrovascular and muscular fitness by increasing energy con-sumption improving insulin sensitivity increasing blood flow increasing the expression of brain‐derived neurotrophic factor and reducing inflammation Western diet which is enriched in refined carbohy-drates (simple sugars) partially hydrogenated oils (peanut corn soybean and canola) and proteins of animal origin (enriched in corn‐based livestock) is high in salt and low in fiber At present in Western diet the ratio of arachidonic acid (ARA) to docosa-hexaenoic acid (DHA) is about 201 By contrast the Paleolithic diet (stone‐age diet) on which our forefathers lived and survived throughout their his-tory contained high amounts of fresh fruits green vegetables lean meats fish seeds piths and barks with ARA to DHA ratio of 11 Long‐term con-sumption of Western diet produces detrimental effect on health not only by inducing an increase in systemic and brain inflammation and oxidative stress through the stimulation of insulin‐like growth factor 1 (IGF‐1) and Toll‐like receptors and generation of high levels of ARA‐derived lipid mediators but also by mediating abnormalities in mitochondrial function along with the induction of

insulin resistance and leptin resistance in visceral organs and the brain The onset and induction of oxidative stress neuroinflammation and abnormal-ities in mitochondrial function are closely associated with impairments in frontal limbic and hippocampal systems leading to changes in learning memory cognition and hedonics In visceral tissues oxidative stress and inflammation along with genetic and environmental factors promote obesity diabetes metabolic syndrome heart disease and cancer These pathological conditions are risk factors for neurological disorders (stroke AD and depression) Thus incidences of neurological disorders are two‐ to threefold higher in patients with type 2 diabetes metabolic syndrome and cardiovascular diseases compared to normal subjects of the same age

The Mediterranean diet which is enriched in fruits vegetables garlic legumes and unrefined cereals and has moderate amount of fish and high amount of olive oil along with modest intake of red wine produces anti‐inflammatory antioxidant and antidiabetic effects leading to cardio‐ and neuroprotection in heart disease and neurological disorders

Exercise initiates the maintenance of good car-diorespiratory cardiovascular cerebrovascular and muscular fitness by preventing metabolic imbalance increasing energy consumption improving insulin sensitivity increasing blood flow elevating levels of brain‐derived neurotrophic factor reducing inflammation and enhancing learning and memory

PREFACE

xx PREFACE

Good nutrition daily exercise and adequate sleep are the foundations for maintaining optimal health

Information on diet and exercise is scattered throughout the literature in the form of original papers reviews and some books These books describe the effects of diet and exercise on visceral organs The purpose of this edited book is to pro-vide readers with a comprehensive and cutting‐edge information on the effects of diet and exercise on cognitive function and age‐related visceral and brain diseases in a manner which is useful not only to students and teachers but also to researchers dietitians nutritionists exercise physiologists and physicians To the best of our knowledge this edited book will be the first to provide a comprehensive description of signal transduction processes associated with the effects of diet and exercise on the cognitive function

This edited book has 28 chapters Chapters 1ndash9 describe the effects of various diet patterns on metabolic changes in visceral organs and the brain Chapters 10ndash26 provide information on the effects of diet and exercise on cognitive function and age‐related neurological disorders Chapter 27 deals

with the role of salt in the pathogenesis of dementia and stroke Finally Chapter 28 deals with perspective on the current progress that will be important for future studies on the effects of diet and exercise on cognitive function in normal subjects and age‐related neurological disorders

Our contributors have tried to ensure uniformity and mode of presentation simple and we have made sure that the progression of subject matter from one topic to another is logical Each chapter provides an extensive bibliography for readers to consult For the sake of simplicity and uniformity a large number of figures with chemical structures of metabolites along with line diagrams of colored signal transduction pathways are included We hope that our attempt to integrate and consolidate the knowledge on the effects of diet and exercise on cognitive function will initiate more studies on molecular mechanisms that link among diet and exercise with cognitive function in normal subjects and patients with age‐related neu-rological disorders

Tahira Farooqui Akhlaq A Farooqui

We thank all the authors of this book who shared their expertise by contributing chapters of a high standard thus making our editorial task much easier We are grateful to Justin Jeffryes Editorial Director at Wiley‐Blackwell for his cooperation and patience during this process We are also

thankful to Stephanie Dollan Senior Editorial Assistant at Wiley‐Blackwell for her professional handling of the manuscript

Tahira FarooquiAkhlaq A Farooqui

ACKNOWLEDGMENTS

Diet and Exercise in Cognitive Function and Neurological Diseases First Edition Edited by Tahira Farooqui and Akhlaq A Farooqui copy 2015 John Wiley amp Sons Inc Published 2015 by John Wiley amp Sons Inc

11 INTRODUCTION

Nutritionndashgene interactions play a pivotal role in cognitive function and neurological disease throughout life Nutrition is one of many environ-mental factors that profoundly alter the phenotypic expression of a given genotype with major impli-cations for development metabolism health and disease [1ndash4] These effects are mediated by changes in expression of multiple genes and can involve epigenetic mechanisms nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence Responses to nutrition are in turn affected by individual genetic variability The effects of nutrition on gene expression are exerted throughout the life cycle with prenatal and early postnatal life being especially critical periods for optimal development Changes in gene expression may be dynamic and short term stable and long term and even heritable between cell divisions and across generations

This review focuses on the following key topics First a short overview is provided on the role of nutrition in cognitive neuroscience Second mecha-nisms underlying nutritionndashgene interactions are discussed especially in relation to the roles of epige-netics and genetic variability in neuroscience

Third attention is focused on the importance of environment and epigenetics in neurological health and disease Finally the role of early nutrition in brain development and later neurological disease is addressed Overall this review highlights the criti-cal importance of nutritionndashgene interactions to optimal neurological function and prevention and treatment of multiple neurological disorders

12 NUTRITION AND COGNITIVE NEUROSCIENCE

The role of nutrition in cognitive neuroscience is highly complex because as with all aspects of nutrition it is multifactorial It is not concerned simply with the impact of a single chemical on the brain but with numerous interactions between multiple nutrients metabolites food and other environmental and genetic factors Nevertheless considerable evidence now links many aspects of nutrition with cognition mental health and well‐being neurological dysfunction and disease [1ndash9] Protective roles are suggested for the Mediterranean diet optimal energy status fish fruits vegetables polyphenols omega‐3 polyunsaturated fatty acids iron zinc copper and numerous vitamins

NUTRITION GENES AND NEUROSCIENCE IMPLICATIONS FOR DEVELOPMENT HEALTH AND DISEASE

Margaret Joy DaunceyWolfson College University of Cambridge Cambridge UK

1

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

Diet and exercise play an important role in maintaining good cognitive function and longevity Macro‐ and micronutrients not only provide energy and building material to the body but also have ability to prevent and protect against age‐related neurological disor-ders Exercise initiates the maintenance of good cardiorespiratory cardiovascular cerebrovascular and muscular fitness by increasing energy con-sumption improving insulin sensitivity increasing blood flow increasing the expression of brain‐derived neurotrophic factor and reducing inflammation Western diet which is enriched in refined carbohy-drates (simple sugars) partially hydrogenated oils (peanut corn soybean and canola) and proteins of animal origin (enriched in corn‐based livestock) is high in salt and low in fiber At present in Western diet the ratio of arachidonic acid (ARA) to docosa-hexaenoic acid (DHA) is about 201 By contrast the Paleolithic diet (stone‐age diet) on which our forefathers lived and survived throughout their his-tory contained high amounts of fresh fruits green vegetables lean meats fish seeds piths and barks with ARA to DHA ratio of 11 Long‐term con-sumption of Western diet produces detrimental effect on health not only by inducing an increase in systemic and brain inflammation and oxidative stress through the stimulation of insulin‐like growth factor 1 (IGF‐1) and Toll‐like receptors and generation of high levels of ARA‐derived lipid mediators but also by mediating abnormalities in mitochondrial function along with the induction of

insulin resistance and leptin resistance in visceral organs and the brain The onset and induction of oxidative stress neuroinflammation and abnormal-ities in mitochondrial function are closely associated with impairments in frontal limbic and hippocampal systems leading to changes in learning memory cognition and hedonics In visceral tissues oxidative stress and inflammation along with genetic and environmental factors promote obesity diabetes metabolic syndrome heart disease and cancer These pathological conditions are risk factors for neurological disorders (stroke AD and depression) Thus incidences of neurological disorders are two‐ to threefold higher in patients with type 2 diabetes metabolic syndrome and cardiovascular diseases compared to normal subjects of the same age

The Mediterranean diet which is enriched in fruits vegetables garlic legumes and unrefined cereals and has moderate amount of fish and high amount of olive oil along with modest intake of red wine produces anti‐inflammatory antioxidant and antidiabetic effects leading to cardio‐ and neuroprotection in heart disease and neurological disorders

Exercise initiates the maintenance of good car-diorespiratory cardiovascular cerebrovascular and muscular fitness by preventing metabolic imbalance increasing energy consumption improving insulin sensitivity increasing blood flow elevating levels of brain‐derived neurotrophic factor reducing inflammation and enhancing learning and memory

PREFACE

xx PREFACE

Good nutrition daily exercise and adequate sleep are the foundations for maintaining optimal health

Information on diet and exercise is scattered throughout the literature in the form of original papers reviews and some books These books describe the effects of diet and exercise on visceral organs The purpose of this edited book is to pro-vide readers with a comprehensive and cutting‐edge information on the effects of diet and exercise on cognitive function and age‐related visceral and brain diseases in a manner which is useful not only to students and teachers but also to researchers dietitians nutritionists exercise physiologists and physicians To the best of our knowledge this edited book will be the first to provide a comprehensive description of signal transduction processes associated with the effects of diet and exercise on the cognitive function

This edited book has 28 chapters Chapters 1ndash9 describe the effects of various diet patterns on metabolic changes in visceral organs and the brain Chapters 10ndash26 provide information on the effects of diet and exercise on cognitive function and age‐related neurological disorders Chapter 27 deals

with the role of salt in the pathogenesis of dementia and stroke Finally Chapter 28 deals with perspective on the current progress that will be important for future studies on the effects of diet and exercise on cognitive function in normal subjects and age‐related neurological disorders

Our contributors have tried to ensure uniformity and mode of presentation simple and we have made sure that the progression of subject matter from one topic to another is logical Each chapter provides an extensive bibliography for readers to consult For the sake of simplicity and uniformity a large number of figures with chemical structures of metabolites along with line diagrams of colored signal transduction pathways are included We hope that our attempt to integrate and consolidate the knowledge on the effects of diet and exercise on cognitive function will initiate more studies on molecular mechanisms that link among diet and exercise with cognitive function in normal subjects and patients with age‐related neu-rological disorders

Tahira Farooqui Akhlaq A Farooqui

We thank all the authors of this book who shared their expertise by contributing chapters of a high standard thus making our editorial task much easier We are grateful to Justin Jeffryes Editorial Director at Wiley‐Blackwell for his cooperation and patience during this process We are also

thankful to Stephanie Dollan Senior Editorial Assistant at Wiley‐Blackwell for her professional handling of the manuscript

Tahira FarooquiAkhlaq A Farooqui

ACKNOWLEDGMENTS

Diet and Exercise in Cognitive Function and Neurological Diseases First Edition Edited by Tahira Farooqui and Akhlaq A Farooqui copy 2015 John Wiley amp Sons Inc Published 2015 by John Wiley amp Sons Inc

11 INTRODUCTION

Nutritionndashgene interactions play a pivotal role in cognitive function and neurological disease throughout life Nutrition is one of many environ-mental factors that profoundly alter the phenotypic expression of a given genotype with major impli-cations for development metabolism health and disease [1ndash4] These effects are mediated by changes in expression of multiple genes and can involve epigenetic mechanisms nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence Responses to nutrition are in turn affected by individual genetic variability The effects of nutrition on gene expression are exerted throughout the life cycle with prenatal and early postnatal life being especially critical periods for optimal development Changes in gene expression may be dynamic and short term stable and long term and even heritable between cell divisions and across generations

This review focuses on the following key topics First a short overview is provided on the role of nutrition in cognitive neuroscience Second mecha-nisms underlying nutritionndashgene interactions are discussed especially in relation to the roles of epige-netics and genetic variability in neuroscience

Third attention is focused on the importance of environment and epigenetics in neurological health and disease Finally the role of early nutrition in brain development and later neurological disease is addressed Overall this review highlights the criti-cal importance of nutritionndashgene interactions to optimal neurological function and prevention and treatment of multiple neurological disorders

12 NUTRITION AND COGNITIVE NEUROSCIENCE

The role of nutrition in cognitive neuroscience is highly complex because as with all aspects of nutrition it is multifactorial It is not concerned simply with the impact of a single chemical on the brain but with numerous interactions between multiple nutrients metabolites food and other environmental and genetic factors Nevertheless considerable evidence now links many aspects of nutrition with cognition mental health and well‐being neurological dysfunction and disease [1ndash9] Protective roles are suggested for the Mediterranean diet optimal energy status fish fruits vegetables polyphenols omega‐3 polyunsaturated fatty acids iron zinc copper and numerous vitamins

NUTRITION GENES AND NEUROSCIENCE IMPLICATIONS FOR DEVELOPMENT HEALTH AND DISEASE

Margaret Joy DaunceyWolfson College University of Cambridge Cambridge UK

1

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

xx PREFACE

Good nutrition daily exercise and adequate sleep are the foundations for maintaining optimal health

Information on diet and exercise is scattered throughout the literature in the form of original papers reviews and some books These books describe the effects of diet and exercise on visceral organs The purpose of this edited book is to pro-vide readers with a comprehensive and cutting‐edge information on the effects of diet and exercise on cognitive function and age‐related visceral and brain diseases in a manner which is useful not only to students and teachers but also to researchers dietitians nutritionists exercise physiologists and physicians To the best of our knowledge this edited book will be the first to provide a comprehensive description of signal transduction processes associated with the effects of diet and exercise on the cognitive function

This edited book has 28 chapters Chapters 1ndash9 describe the effects of various diet patterns on metabolic changes in visceral organs and the brain Chapters 10ndash26 provide information on the effects of diet and exercise on cognitive function and age‐related neurological disorders Chapter 27 deals

with the role of salt in the pathogenesis of dementia and stroke Finally Chapter 28 deals with perspective on the current progress that will be important for future studies on the effects of diet and exercise on cognitive function in normal subjects and age‐related neurological disorders

Our contributors have tried to ensure uniformity and mode of presentation simple and we have made sure that the progression of subject matter from one topic to another is logical Each chapter provides an extensive bibliography for readers to consult For the sake of simplicity and uniformity a large number of figures with chemical structures of metabolites along with line diagrams of colored signal transduction pathways are included We hope that our attempt to integrate and consolidate the knowledge on the effects of diet and exercise on cognitive function will initiate more studies on molecular mechanisms that link among diet and exercise with cognitive function in normal subjects and patients with age‐related neu-rological disorders

Tahira Farooqui Akhlaq A Farooqui

We thank all the authors of this book who shared their expertise by contributing chapters of a high standard thus making our editorial task much easier We are grateful to Justin Jeffryes Editorial Director at Wiley‐Blackwell for his cooperation and patience during this process We are also

thankful to Stephanie Dollan Senior Editorial Assistant at Wiley‐Blackwell for her professional handling of the manuscript

Tahira FarooquiAkhlaq A Farooqui

ACKNOWLEDGMENTS

Diet and Exercise in Cognitive Function and Neurological Diseases First Edition Edited by Tahira Farooqui and Akhlaq A Farooqui copy 2015 John Wiley amp Sons Inc Published 2015 by John Wiley amp Sons Inc

11 INTRODUCTION

Nutritionndashgene interactions play a pivotal role in cognitive function and neurological disease throughout life Nutrition is one of many environ-mental factors that profoundly alter the phenotypic expression of a given genotype with major impli-cations for development metabolism health and disease [1ndash4] These effects are mediated by changes in expression of multiple genes and can involve epigenetic mechanisms nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence Responses to nutrition are in turn affected by individual genetic variability The effects of nutrition on gene expression are exerted throughout the life cycle with prenatal and early postnatal life being especially critical periods for optimal development Changes in gene expression may be dynamic and short term stable and long term and even heritable between cell divisions and across generations

This review focuses on the following key topics First a short overview is provided on the role of nutrition in cognitive neuroscience Second mecha-nisms underlying nutritionndashgene interactions are discussed especially in relation to the roles of epige-netics and genetic variability in neuroscience

Third attention is focused on the importance of environment and epigenetics in neurological health and disease Finally the role of early nutrition in brain development and later neurological disease is addressed Overall this review highlights the criti-cal importance of nutritionndashgene interactions to optimal neurological function and prevention and treatment of multiple neurological disorders

12 NUTRITION AND COGNITIVE NEUROSCIENCE

The role of nutrition in cognitive neuroscience is highly complex because as with all aspects of nutrition it is multifactorial It is not concerned simply with the impact of a single chemical on the brain but with numerous interactions between multiple nutrients metabolites food and other environmental and genetic factors Nevertheless considerable evidence now links many aspects of nutrition with cognition mental health and well‐being neurological dysfunction and disease [1ndash9] Protective roles are suggested for the Mediterranean diet optimal energy status fish fruits vegetables polyphenols omega‐3 polyunsaturated fatty acids iron zinc copper and numerous vitamins

NUTRITION GENES AND NEUROSCIENCE IMPLICATIONS FOR DEVELOPMENT HEALTH AND DISEASE

Margaret Joy DaunceyWolfson College University of Cambridge Cambridge UK

1

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

We thank all the authors of this book who shared their expertise by contributing chapters of a high standard thus making our editorial task much easier We are grateful to Justin Jeffryes Editorial Director at Wiley‐Blackwell for his cooperation and patience during this process We are also

thankful to Stephanie Dollan Senior Editorial Assistant at Wiley‐Blackwell for her professional handling of the manuscript

Tahira FarooquiAkhlaq A Farooqui

ACKNOWLEDGMENTS

Diet and Exercise in Cognitive Function and Neurological Diseases First Edition Edited by Tahira Farooqui and Akhlaq A Farooqui copy 2015 John Wiley amp Sons Inc Published 2015 by John Wiley amp Sons Inc

11 INTRODUCTION

Nutritionndashgene interactions play a pivotal role in cognitive function and neurological disease throughout life Nutrition is one of many environ-mental factors that profoundly alter the phenotypic expression of a given genotype with major impli-cations for development metabolism health and disease [1ndash4] These effects are mediated by changes in expression of multiple genes and can involve epigenetic mechanisms nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence Responses to nutrition are in turn affected by individual genetic variability The effects of nutrition on gene expression are exerted throughout the life cycle with prenatal and early postnatal life being especially critical periods for optimal development Changes in gene expression may be dynamic and short term stable and long term and even heritable between cell divisions and across generations

This review focuses on the following key topics First a short overview is provided on the role of nutrition in cognitive neuroscience Second mecha-nisms underlying nutritionndashgene interactions are discussed especially in relation to the roles of epige-netics and genetic variability in neuroscience

Third attention is focused on the importance of environment and epigenetics in neurological health and disease Finally the role of early nutrition in brain development and later neurological disease is addressed Overall this review highlights the criti-cal importance of nutritionndashgene interactions to optimal neurological function and prevention and treatment of multiple neurological disorders

12 NUTRITION AND COGNITIVE NEUROSCIENCE

The role of nutrition in cognitive neuroscience is highly complex because as with all aspects of nutrition it is multifactorial It is not concerned simply with the impact of a single chemical on the brain but with numerous interactions between multiple nutrients metabolites food and other environmental and genetic factors Nevertheless considerable evidence now links many aspects of nutrition with cognition mental health and well‐being neurological dysfunction and disease [1ndash9] Protective roles are suggested for the Mediterranean diet optimal energy status fish fruits vegetables polyphenols omega‐3 polyunsaturated fatty acids iron zinc copper and numerous vitamins

NUTRITION GENES AND NEUROSCIENCE IMPLICATIONS FOR DEVELOPMENT HEALTH AND DISEASE

Margaret Joy DaunceyWolfson College University of Cambridge Cambridge UK

1

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

Diet and Exercise in Cognitive Function and Neurological Diseases First Edition Edited by Tahira Farooqui and Akhlaq A Farooqui copy 2015 John Wiley amp Sons Inc Published 2015 by John Wiley amp Sons Inc

11 INTRODUCTION

Nutritionndashgene interactions play a pivotal role in cognitive function and neurological disease throughout life Nutrition is one of many environ-mental factors that profoundly alter the phenotypic expression of a given genotype with major impli-cations for development metabolism health and disease [1ndash4] These effects are mediated by changes in expression of multiple genes and can involve epigenetic mechanisms nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence Responses to nutrition are in turn affected by individual genetic variability The effects of nutrition on gene expression are exerted throughout the life cycle with prenatal and early postnatal life being especially critical periods for optimal development Changes in gene expression may be dynamic and short term stable and long term and even heritable between cell divisions and across generations

This review focuses on the following key topics First a short overview is provided on the role of nutrition in cognitive neuroscience Second mecha-nisms underlying nutritionndashgene interactions are discussed especially in relation to the roles of epige-netics and genetic variability in neuroscience

Third attention is focused on the importance of environment and epigenetics in neurological health and disease Finally the role of early nutrition in brain development and later neurological disease is addressed Overall this review highlights the criti-cal importance of nutritionndashgene interactions to optimal neurological function and prevention and treatment of multiple neurological disorders

12 NUTRITION AND COGNITIVE NEUROSCIENCE

The role of nutrition in cognitive neuroscience is highly complex because as with all aspects of nutrition it is multifactorial It is not concerned simply with the impact of a single chemical on the brain but with numerous interactions between multiple nutrients metabolites food and other environmental and genetic factors Nevertheless considerable evidence now links many aspects of nutrition with cognition mental health and well‐being neurological dysfunction and disease [1ndash9] Protective roles are suggested for the Mediterranean diet optimal energy status fish fruits vegetables polyphenols omega‐3 polyunsaturated fatty acids iron zinc copper and numerous vitamins

NUTRITION GENES AND NEUROSCIENCE IMPLICATIONS FOR DEVELOPMENT HEALTH AND DISEASE

Margaret Joy DaunceyWolfson College University of Cambridge Cambridge UK

1

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

2 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

There are many inconsistencies between studies in part because of methodological differences associ-ated with the multifactorial nature of the subject However taken together strong evidence clearly links optimal energy status and the Mediterranean diet with optimal cognitive function and prevention of cognitive decline and neurological dysfunction

121 Specific Nutrients

Clearly it is difficult to assess the precise benefits of specific nutrients on neurological and cognitive function Nevertheless significant links have been reported in studies on many nutrients including long‐chain polyunsaturated fatty acids vitamins AndashE and trace elements [1 4 8 10ndash16] Interactions and synergism between specific nutri-ents are especially important and may help in part to explain inconsistencies between studies and the importance of an optimal balanced diet

Despite some controversy substantial evidence suggests a vital role of omega‐3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neurodevelopment cognition mental health and neurodegeneration They enhance memory mood and behavior and reduce depression By contrast deficiency of omega‐3 fatty acids is linked with increased risk of attention‐deficithyperactivity disorder depression dementia Alzheimerrsquos disease and schizophrenia Moreover diets high in trans and saturated fats adversely affect cognitive function The balance between omega‐3 and omega‐6 fatty acid intakes may be especially critical for optimal mental health Competitive inhibition occurs between these two groups of fatty acids and Western diets low in omega‐3 and high in omega‐6 may contribute to reduced accretion of DHA inhibition of secondary neurite growth and impaired brain development and function

Trace elements including copper zinc and iron are important in neurodevelopment neurotrans-mitter synthesis and energy metabolism and have key roles in cognition Low plasma copper is linked with cognitive decline and zinc deficiency is linked with attention‐deficithyperactivity disorder in children impaired memory and learning in ado-lescents and stress depression and cognitive decline in adults There is a fine balance between the beneficial and harmful effects of many trace elements and interactions between trace elements are important for optimal brain function These

may be especially important during critical stages of development and periods of vulnerability to neurological diseases

122 Mediterranean Diet

It is increasingly apparent that the overall balance of specific nutrients and foods in the diet is impor-tant for optimal function In relation to cognition and prevention of neurological disorders a protective role has been reported for fish fruit and vegetables Considerable attention is now focused on defining an optimal balanced diet and future studies should improve understanding of optimal nutrition throughout the life course In this context the traditional Mediterranean diet is regarded as especially beneficial [17 18] It is characterized by high intakes of vegetables fruits cereals fish and unsaturated fats such as olive oil a low to moderate intake of wine during meals and low intakes of red and processed meats dairy foods and saturated fats Higher adherence to this diet may contribute to the prevention of several brain disorders including depression cognitive impairment Alzheimerrsquos dis-ease and Parkinsonrsquos disease However it is also apparent that suboptimal energy status and overnu-trition even of an optimal Mediterranean diet are not beneficial to neurological function and the importance of energy status is therefore discussed in Section 123

123 Energy Status

Many studies link energy status with cognitive function and neurological disorders The term energy status is used here to include energy intake physical activity energy metabolism and related changes in body composition It is a broader and less precise term than energy balance and reflects the multifaceted influence of this critical compo-nent of nutrition Moreover in some studies it can be difficult to determine whether effects on brain function are due to changes in energy intake andor energy expenditure studies on physical activity do not always control energy intake while those on energy intake do not always control physical activity

The interactions between energy status and cog-nition are multifactorial and complex Nevertheless evidence highlights close links between energy status and mental health [1 4 19 20] Physical activity is beneficial to mental health and

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

NUTRITION GENES AND NEUROSCIENCE 3

well‐being it decreases the risk of depression and improves mood and self‐esteem Regular aerobic exercise increases brain volume and reduces the risk of cognitive impairment dementia and Alzheimerrsquos disease in older adults Undernutrition without mal-nutrition reduces age‐related deficits in cognitive function whereas overnutrition can result in cognitive dysfunction

High‐energy diets and a sedentary lifestyle are leading to increased prevalence of obesity and diabetes There is a link between these conditions and risk of impaired cognitive function depression and dementia that is age related [21 22] obesity in midlife years 40ndash50s is linked with increased dementia whereas by the late 70s the risk has inverted and obesity may even be protective of dementia Moreover patients with severe mental illness such as schizophrenia are at greater risk of metabolic syndrome and associated obesity type 2 diabetes and dyslipidemia [23] Mechanisms involving chronic inflammation cell signaling pathways metabolic dysfunction and genetic factors also link overnutrition with numerous disor-ders including Alzheimerrsquos disease [24] Indeed Alzheimerrsquos can be regarded as a neuroendocrine degenerative disorder that has elements of both insulininsulin‐like growth factor (IGF) resistance and insulin deficiency suggesting that it be referred to as ldquotype 3 diabetesrdquo [25]

13 MECHANISMS UNDERLYING NUTRITIONndashGENE INTERACTIONS

Nutrition affects neurological function and cogni-tion via numerous influences on cell membranes enzymes neurotransmitters metabolism neurogen-esis and synaptic plasticity Many of these diverse effects are mediated by expression of multiple genes and associated regulatory networks An additional layer of complexity is provided by individual genetic variability the differences in protein‐coding and noncoding regions of the genome have major influences on individual response to nutrition

The term ldquonutritional genomicsrdquo is often used interchangeably with ldquonutrigenomicsrdquo and involves the study of nutritionndashgene interactions This includes both the effects of nutrition on gene expression (ldquonutrigenomicsrdquo) and the effects of genetic variability on responses to nutrition (ldquonutrigeneticsrdquo) [2 26 27] Figure 11 outlines key mechanisms involved in nutritionndashgene interactions

131 Nutritional Regulation of Gene Expression

Considerable progress is to be made in understanding the molecular mechanisms and neural pathways underlying the effects of nutrition on gene expression [2 4 6 24 28 29] Cellular and nuclear receptors play a key role in mediating the effects of nutrition on numerous genes involved in neural function and brain plasticity

Nutrition has both direct and indirect effects on gene expression with the latter being exerted via cell signaling pathways In relation to direct effects many nutrients and metabolites are ligands for nuclear receptorstranscription factors for example vitamin A (retinoic acid receptor RAR) vitamin D (vitamin D receptor VDR) vitamin E (pregnane X receptor PXR) calcium (calcineurin) zinc (metal‐responsive transcription factor 1 MTF1) and fatty acids (perox-isome proliferator‐activated receptors PPARs sterol regulatory element‐binding proteins SREBPs)

In relation to indirect effects energy status influ-ences numerous hormones and growth factors that act as nutritional sensors to influence the brain via changes in gene expression Polypeptide hormones including growth hormone IGFs insulin and brain‐derived neurotrophic factor (BDNF) act on plasma membrane‐bound receptors to trigger gene transcrip-tion via intracellular signaling pathways Lipophilic hormones including thyroid hormones and glucocor-ticoids act on their nuclear receptors to regulate the expression of transcription of multiple genes via DNA binding and chromatin remodeling Epigenetic mechanisms are involved in many of these responses and these are discussed in the next section

NutritionGene

expression

Gene variability

Mutations Single nucleotidepolymorphisms

(SNPs)

Copy numbervariants(CNVs)

Transient or stablerole of epigenetics

Fig 11 Overview of nutritionndashgene interactions Modified from Dauncey MJ Recent advances in nutrition genes and brain health Proceedings of the Nutrition Society 2012 71 581ndash591

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

4 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

132 Epigenetics Definition and Mechanisms

Nutrition affects gene expression at levels of transcription translation and posttranslational modifications and epigenetic mechanisms play a key role in some of these responses These link nutrition with outcome in relation to health or disease Many factors act as powerful influences on the epigenetic regulation of gene expression including nutrition age gender physiological and psychological stress chemi-cals and infections Thus the epigenome provides a critical layer of regulation nutrition is one of many epigenetic regulators that can modify gene expression and hence phenotypic expression [3 4 30]

The term epigenetics means ldquoabove geneticsrdquo and includes mechanisms that alter gene expression without changes in DNA sequence Precise defini-tions vary widely investigations may be concerned with transient or stable effects with the latter sometimes involving heritable changes between generations Epigenetic mechanisms often involve chemical marking of chromatin that is the form in which DNA is packaged with histone proteins in the cell nucleus Epigenetic marks can induce chromatin remodeling and related changes in gene expression They include DNA methylation which reduces gene activity and histone modifications such as acetyla-tion which increases gene activity

Additional epigenetic mechanisms involve non‐protein‐coding RNAs (ncRNAs) RNA editing telomere control and chromosomal position effects Although protein‐coding genes are the subject of many functional studies most of the genome gives rise to ncRNAs that play key roles in development health and disease [3 31ndash33] Detailed investiga-tions have revealed a central role for ncRNAs as regulators of transcription epigenetic processes and gene silencing Moreover there are key interac-tions between ncRNAs and environmental factors such as nutrition [3 34 35] Multiple gene variants in protein‐coding and noncoding regions of the genome add a further level of control

133 Gene Variability and Individual Responses to Nutrition

Individual differences in gene variability can affect gene expression phenotype responses to environ-ment and risk of neurological disorders [2 3 27 36] Gene variants include mutations single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) These have the ability to markedly affect the extent to which nutrition influences gene expression

Mutations involve a change in DNA sequence that may result in a loss or change in gene function They can be linked with rare single gene disorders such as phenylketonuria By contrast common gene variants involving a change of a single nucle-otide in at least 1 of the population are termed SNPs They have a key role in individual responses to nutrition and are linked with many polygenic common disorders in humans the combined action of alleles from several genes increases the risk of obesity diabetes cancers cardiovascular disease and neurological disorders

Genome‐wide association studies (GWAS) on large numbers of individuals are significantly advancing understanding of the role of SNPs in responses to nutrition For example a physically active lifestyle is associated with a 40 reduction in the genetic predisposition to obesity [37] This find-ing resulted from genotyping 12 SNPs in obesity‐associated loci in a study involving more than 20000 people Of additional significance are findings from a recent GWAS of metabolic traits that reveals novel links between gene metabolites and disease [38]

Common gene variants such as SNPs also affect epigenetic mechanisms and hence individual responses to nutrition and susceptibility to disease A study of genetic and nongenetic influences dur-ing pregnancy on infant global and site‐specific DNA methylation highlights important roles for folate gene variants and vitamin B12 status of infants and mothers [39]

By contrast with SNPs CNVs are structural gene variants that involve multiple copies or deletions of large parts of the genome They are either inherited or resulted from de novo mutation occur in genes parts of genes and outside genes and thus can profoundly affect RNA and protein expression These common insertions or deletions account for much of the genetic variability between people and are often linked with genes involved in moleculendashenvironment interactions The extent to which CNVs are involved in neurological disorders is the subject of considerable interest [40 41]

14 ENVIRONMENT AND EPIGENETICS IN NEUROLOGICAL HEALTH AND DISEASE

Numerous disorders of mental health and neurology are linked with interactions between multiple genetic and environmental factors including nutrition It is

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

NUTRITION GENES AND NEUROSCIENCE 5

now appreciated that epigenetic mechanisms are involved in many of these actions and these are discussed in the following sections

141 Epigenetics Development and Metabolism

Many epigenetic processes play a critical role in neurological development plasticity learning and memory [2ndash4 42ndash44] Epigenetics is a part of normal development and a single genome gives rise to multiple cell‐specific epigenomes in differ-ent tissues and organs This explains the pheno-typic diversity of adult differentiated cells that arise from identical genomes Moreover neuronal activity can alter the epigenetic state of neuronal genes and in turn these epigenetic changes can influence the future responses of neurons and hence have important consequences for brain function and dysfunction [45]

Development is operated by reversible epige-netic memories with global DNA methylation and demethylation occurring over time [46] As a part of normal development in germ cells and early embryos there are striking genome‐wide removal and subsequent reestablishment of epigenetic information Of particular significance was the real-ization that epigenetic mechanisms are reversible [47] Not only do reversible epigenetic memories play a key role in development but they are a mech-anism by which nutritional factors could be used to ameliorate the effects of adverse environmental experience

Metabolic mechanisms are also involved in epi-genetic regulation [48] Endogenous metabolites and cofactors regulate the activity of chromatin‐modifying enzymes providing a direct link between epigenetics and the cellrsquos metabolic state Integration of understanding in genomic epigenomics and met-abolic regulatory mechanisms may further elucidate the role of nutrition in neurological function and dysfunction and provide new approaches to modu-lation of epigenetic processes for prevention and therapy

142 Energy Status Signaling Molecules and Cognitive Function

Optimal mental health is associated with positive advantages including a general state of well‐beingmdashthe ability to learn interact with others and cope with change and uncertainty Cultural

social economic and environmental factors such as nutrition all contribute to mental health cognitive function and quality of life

Many nutritional effects on cognition are medi-ated by changes in expression of multiple genes and associated regulatory networks [2 3 6 49] This involves effects on cell membranes enzymes neurotransmitters metabolism neurogenesis and synaptic plasticity Multiple nutritionndashgene interac-tions are involved in these responses Especially important for example are links between energy status and BDNF This molecule is involved in prenatal and adult neurogenesis in the growth differentiation and survival of neurons and synapses and in synaptic plasticity BDNF has a critical role in the cerebral cortex and hippocampus and is vital for learning memory and cognition

The beneficial effects of physical activity on mental health and cognition can be explained in part by induction of BDNF gene expression in the hippocampus and nutrition can add to these effects Moreover the adverse effects of strenuous exercise or high‐energy intake are related to an increase in reactive oxygen species decrease in BDNF expres-sion and compromised synaptic plasticity and cognition

Many other signaling molecules are also impli-cated in nutritional regulation of brain function IGF‐1 mediates the actions of BDNF and the his-tone deacetylase sirtuin silent information regu-lator 1 (SIRT1) is modified by energy metabolism Glucocorticoids thyroid hormones vitamins A and D polyunsaturated fatty acids and other ligands of the nuclear receptor superfamily may also play a pivotal role Their receptors act as transcription factors to affect multiple genes via epigenetic changes involving histone acetylation and chromatin remodeling

The circulatory systemic environment acts as a modulator of neurogenesis and brain aging with the aging systemic milieu negatively regulating cognitive function [50] Recent studies in mice have shown that young blood reverses age‐related impairments in synaptic plasticity and cognitive function [51] Systemic factors in young blood induce vascular and neurogenic rejuvenation in the aging mouse brain Moreover growth differentiation factor 11 (GDF11) can alone improve the cerebral vasculature and enhance neu-rogenesis [52] GDF11 is a member of the trans-forming growth factor β (TGF‐β) family and its nutritional regulation at all life stages needs to be

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological

6 DIET AND EXERCISE IN COGNITIVE FUNCTION AND NEUROLOGICAL DISEASES

investigated Overall the studies discussed in this section suggest novel approaches for prevention and therapy of neurological disorders

143 Neuroepigenetics and Neurological Disorders

The field of neuroepigenetics has had a considerable impact on understanding of brain function and neuro-logical disorders [3 4 42 53ndash56] Environmental modulation of epigenetic mechanisms is implicated in the onset and course of many neurological condi-tions including autism eating disorders depression Parkinsonrsquos disease Huntingtonrsquos disease multiple sclerosis cognitive decline dementia Alzheimerrsquos disease and schizophrenia Epigenetic mechanisms can mediate immediate and long‐term responses to adverse experience such as malnutrition and physiological stress to affect disease susceptibility and the course of neurodegenerative events

Alzheimerrsquos Disease Evidence suggests that com-plex epigenetic modifications are involved in Alzheimerrsquos disease confirming that environmental factors play a key role in this devastating disorder [3 42 57 58] Indeed epigenetic mechanisms may provide a unique integrative framework for the path-ologic diversity and complexity of Alzheimerrsquos [59]

Epigenetic changes in the brains of Alzheimerrsquos patients and in models of the disease involve DNA methylation histone modifications and noncoding microRNAs at multiple loci Genome‐wide results indicate decreases in DNA methylation markers in cortical neurons from Alzheimerrsquos patients com-pared with elderly controls whereas there are no such changes in the cerebellum a region that is relatively spared in Alzheimerrsquos

The extent to which epigenetic changes in Alzheimerrsquos disease and in normal aging are linked with nutrition is the subject of considerable current interest [4] Specific nutrients including the dietary methyl donors folate vitamins B6 and B12 choline and methionine are essential for DNA methylation and optimal brain development and function The probability is that nutrition throughout life markedly influences epigenetic marks in the brain with con-comitant effects on a wide range of neurological conditions including dementia

The approval of epigenetic drugs for cancer treatment is advancing progress in the development of epigenetic drugs for treating neurodegenerative diseases including Alzheimerrsquos [60 61] Methyl

donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders In the longer term it may also be possible to use targeted nutritional intervention to prevent or ameliorate adverse epigenetic marks involved in the pathogenesis and pathology of the disease

Schizophrenia Schizophrenia is a severe mental disorder with symptoms that include profound disrup-tions in thinking hallucinations and delusions and social and emotional dysfunction The peak age of onset is in the 20s to early 30s and it is associated with substantial costs At the personal level there are often unemployment poverty and homelessness Life expectancy is reduced by 12ndash15 years because of the sedentary lifestyle obesity smoking and suicide Economically the costs associated with schizophrenia can be greater than for all cancers combined

Causes of schizophrenia are multifactorial and involve numerous interactions between genetic and environmental factors [2 62 63] Epigenetic mech-anisms are implicated in these interactions although knowledge of the role of epigenetics in this field is limited and therefore should be interpreted with caution [64] Nevertheless genome‐wide analysis on postmortem brain tissue suggests that differential DNA methylation is important in schizophrenia etiology [65]

Many environmental factors have been linked with schizophrenia including diet place and time of birth infections obstetric factors prenatal and psychosocial stress chemicals drugs and paternal age The probability is that early‐life environment plays a key role in schizophrenia and many other neurological disorders Indeed it is increasingly considered a neurodevelopmental disorder [56] The neurodevelopmental hypothesis proposes schizo-phrenia to be related to genetic and environmental factors leading to abnormal brain development dur-ing the prenatal or postnatal period Moreover first disease symptoms appear in early adulthood during the synaptic pruning and myelination process

15 EARLY NUTRITION BRAIN DEVELOPMENT AND LATER NEUROLOGICAL DISEASE

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neurosci-ence Optimal nutrition is essential for neurological