The Modulation of Age-Related Cognitive Decline and

Neurodegenerative Disease Via Fruits and Vegetables: The Longevity

Dividend

The Modulation of AgeThe Modulation of Age--Related Related Cognitive Decline and Cognitive Decline and

Neurodegenerative Disease Via Fruits Neurodegenerative Disease Via Fruits and Vegetables: The Longevity and Vegetables: The Longevity

DividendDividend

James A. Joseph Barbara ShukittJames A. Joseph Barbara Shukitt--Hale, Hale, Derek FisherDerek Fisher

Neuroscience LaboratoryNeuroscience LaboratoryUSDA Human Nutrition Research Center on AgingUSDA Human Nutrition Research Center on Aging

Tufts UniversityTufts UniversityBoston, MassachusettsBoston, Massachusetts

AgingAgingAging

Aging can be defined as a condition where stressors are not counteracted by protective functions leading to a dysregulation in development. In the neuroscience world it is characterized by losses in neuronal function accompanied by behavioral declines(decreases in motor and cognitive performance) in both humans and animals

Cognitive and Motor behavior changes in senescence

Cognitive and Motor behavior Cognitive and Motor behavior changes in senescencechanges in senescence

Motor: inclined screen, Motor: inclined screen, rotorodrotorod, planks of various , planks of various widths, wire suspension. These assess balance widths, wire suspension. These assess balance strength and coordination.strength and coordination.

Cognitive: short term and long term memories as Cognitive: short term and long term memories as assessed via a Morris water mazeassessed via a Morris water maze

Motor TasksMotor Tasks

66

Rotarod TestRat Age StudyRotarodRotarod TestTestRat Age StudyRat Age Study

Age (months)Age (months)

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*Means with different letters are significantly different from each other (P<.05).Shukitt-Hale et al. Exp Gerontol. 1998;33:615-624.

OXIDATIVE STRESS AND INFLAMMATION THE “EVIL” GEMINI TWINS OF BRAIN AGING I.

OXIDATIVE STRESS AND INFLAMMATION THE OXIDATIVE STRESS AND INFLAMMATION THE ““EVILEVIL”” GEMINI GEMINI TWINS OF TWINS OF BRAIN AGING I.BRAIN AGING I.

THE BRAIN UTILIZES 20% OF THE BODYTHE BRAIN UTILIZES 20% OF THE BODY’’S OXYGEN AT REST S OXYGEN AT REST ––HIGHER AMOUNTS DURING PROBLEM SOLVING.HIGHER AMOUNTS DURING PROBLEM SOLVING.Decreases in antioxidant protection:Decreases in antioxidant protection:•• 1. Increases in the ratio of oxidized to total glutathione 1. Increases in the ratio of oxidized to total glutathione

((OlanowOlanow, 1992). , 1992). •• 2. Alterations in 2. Alterations in redoxredox active iron (e.g., see Savory, et active iron (e.g., see Savory, et

al., 1999; al., 1999; GilissenGilissen et al., 1999). et al., 1999). •• 3. Significant 3. Significant lipofuscinlipofuscin accumulation (accumulation (GilissenGilissen et al., et al.,

1999).1999).•• 4. Reduced glutamine 4. Reduced glutamine synthetasesynthetase (Carney et al., 1994).(Carney et al., 1994).

OXIDATIVE STRESS AND INFLAMMATION THE “EVIL” GEMINI TWINS OF BRAIN AGING II.

OXIDATIVE STRESS AND INFLAMMATION THE OXIDATIVE STRESS AND INFLAMMATION THE ““EVILEVIL”” GEMINI GEMINI TWINS OF TWINS OF BRAIN AGING II.BRAIN AGING II.

Alterations in markers of inflammation:Alterations in markers of inflammation:•• 1. Increased cytokines (e.g., TNF alpha, IL1. Increased cytokines (e.g., TNF alpha, IL--1 beta 1 beta

production has been detected in CNS in brain injury and production has been detected in CNS in brain injury and AD (AD (RosenmanRosenman et al., 1995; et al., 1995; WoodroofeWoodroofe, 1995). , 1995).

•• 2. Activation of 2. Activation of microglialmicroglial cells. (cells. (DiPatreDiPatre& Gellman 1997 & Gellman 1997 Hong et al., 2006).Hong et al., 2006).

Changes in the vulnerability of specific Changes in the vulnerability of specific muscarinicmuscarinic receptor receptor subtypes to oxidative and inflammatory stressors (Joseph subtypes to oxidative and inflammatory stressors (Joseph and Fisher 2002; 2003).and Fisher 2002; 2003).

Possible Prevention of Alzheimer’s Disease:

Dietary Considerations

Possible Prevention of AlzheimerPossible Prevention of Alzheimer’’s s Disease: Disease:

Dietary ConsiderationsDietary ConsiderationsConsumption of fish, fish oils, etc, containing n3 DHA or EPAConsumption of fish, fish oils, etc, containing n3 DHA or EPA11

CurcuminCurcumin2,32,3

MelatoninMelatonin44

Folic acid, vitamin B complex, especially in persons with high Folic acid, vitamin B complex, especially in persons with high homocysteine levelshomocysteine levels55

Use of vitamin E, and/or vitamin C in enriched foods or Use of vitamin E, and/or vitamin C in enriched foods or supplementssupplements66

Alpha lipoic acid and L carnitine supplementsAlpha lipoic acid and L carnitine supplements77

High antioxidant fruits and vegetablesHigh antioxidant fruits and vegetables88

1. Young et al. 1. Young et al. ReprodReprod NutrNutr DevDev. 2005;45:1. 2005;45:1--28 (B); 2. Lim et al. 28 (B); 2. Lim et al. J NeurosciJ Neurosci. 2001;21:8370. 2001;21:8370--8377 (B); 8377 (B); 3. Ringman et al. 3. Ringman et al. Curr Alzheimer ResCurr Alzheimer Res. 2005;2:131. 2005;2:131--136 (B); 4. Wu et al. 136 (B); 4. Wu et al. J Pineal ResJ Pineal Res. 2005;38:145. 2005;38:145--152 (B); 152 (B); 5. Anello et al. 5. Anello et al. NeuroreportNeuroreport. 2004;15:859. 2004;15:859--861 (B); 6. Zandi et al. 861 (B); 6. Zandi et al. Arch Arch NeurolNeurol. 2004;61:82. 2004;61:82--88 (B); 88 (B); 7. Rogers et al. 7. Rogers et al. Age AgeingAge Ageing. 1999;28:205. 1999;28:205--209 (B); 8. Joseph et al. 209 (B); 8. Joseph et al. Am J Clin Am J Clin NutrNutr. 2005;81(1 suppl):. 2005;81(1 suppl):313S313S--316S (B); Adapted from 316S (B); Adapted from JanssonJansson. . Med HypothesesMed Hypotheses. 2005;64:960. 2005;64:960--967 (B).967 (B).

Quenching the Fire!Using Grapes and Berries to

Changing the Neuronal Environment to Alter Signaling

and Behavior

Quenching the Fire!Quenching the Fire!Using Grapes and Berries to Using Grapes and Berries to

Changing the Neuronal Changing the Neuronal Environment to Alter Signaling Environment to Alter Signaling

and Behaviorand Behavior

Fruit PolyphenolicsFruit Fruit PolyphenolicsPolyphenolics

AnthocyaninsAnthocyaninsFlavonolsFlavonolsProanthocyanidinsProanthocyanidinsCatechinsCatechins

PhenolicsPhenolics

FlavonoidsFlavonoidsHydroxycinnamatesHydroxycinnamates

Simple Simple PhenolicsPhenolics

Courtesy of W. Courtesy of W. KaltKalt, Ph.D., Ph.D.

Reversal of Age-Related Changes in Neuronal Function and Behavior Through Dietary Supplementation: Major Findings

Reversal of AgeReversal of Age--Related Changes in Related Changes in Neuronal Function and Behavior Through Neuronal Function and Behavior Through Dietary Supplementation: Major FindingsDietary Supplementation: Major Findings

The supplemented diets reversed decrements inThe supplemented diets reversed decrements inNeuronal function, Neuronal function, egeg,,

Striatal calcium sequestrationStriatal calcium sequestrationCerebellar noradrenergic sensitivityCerebellar noradrenergic sensitivityMuscarinic receptor sensitivityMuscarinic receptor sensitivity

BehaviorBehaviorMorris water maze performanceMorris water maze performanceMotor behavioral performance (rod walking, Motor behavioral performance (rod walking, accelerodaccelerod))In motor behavioral learning BickfordIn motor behavioral learning BickfordIn exploration of a novel environment In exploration of a novel environment MalinMalin

Joseph et al. Am J Clin Nutr. 2005;81(1 suppl):313S-316S.

•GRAPE JUICE CONCENTRATION

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Other Fruits (nuts) and Veggies That Alter Behavioral Deficits in Aging In

Addition to Blueberries

Other Fruits (nuts) and Veggies That Other Fruits (nuts) and Veggies That Alter Behavioral Deficits in Aging In Alter Behavioral Deficits in Aging In

Addition to BlueberriesAddition to BlueberriesMemoryMemory

SpinachSpinachStrawberriesStrawberriesCranberriesCranberriesBlack currantsBlack currantsConcord grape juiceConcord grape juicePlum juicePlum juiceBlackberriesBlackberriesWalnutsWalnuts

MotorMotorCranberriesCranberriesConcord grape juiceConcord grape juiceStrawberriesStrawberriesBlackberriesBlackberriesWalnutsWalnuts

Possible Mechanisms in the Beneficial Effects of the Berry and

Grape Polyphenolics

Possible Mechanisms in the Possible Mechanisms in the Beneficial Effects of the Berry and Beneficial Effects of the Berry and

Grape Grape PolyphenolicsPolyphenolicsFunctional antioxidant effects/antiFunctional antioxidant effects/anti--inflammatory effectsinflammatory effects

Decreased sensitivity to oxidative stressDecreased sensitivity to oxidative stressDecreased sensitivity to neurotoxins and inflammatory Decreased sensitivity to neurotoxins and inflammatory

agentsagentsIncreased calcium clearanceIncreased calcium clearanceMembrane effects.Membrane effects.Alterations in signalingAlterations in signaling

•• Decreased inflammatory signalingDecreased inflammatory signaling••Decreased oxidative stress signalingDecreased oxidative stress signaling•• Increased protective signalingIncreased protective signaling•• Signaling in learning and memorySignaling in learning and memory

6262

ROSROS

PKCPKCγγ

IGFIGF--11

PKAPKA

RASRAS

pp38MAPKpp38MAPK

CREBCREBARCARC

NFKBNFKB

ROSROSROSROS ROSROS

BBSBBS

P53,P53,CaspasesCaspases

――――

MITOCHONDRIAMITOCHONDRIA

JNK

TNFα, Il-1β, COX-2, iNOS

B. Anti - OS/InflammatoryA. Pro Survival

ERK

BBS

Elk-1

AKT

GSK3βDirect ROS Scavenging

Inactivationof BAD

Bcl 2

2121

GodGodGodNeuroscience LabNeuroscience Lab

B. ShukittB. Shukitt--HaleHale

D. D. BielinskiBielinski, ,

D. FisherD. Fisher

V. ChengV. Cheng

CollaboratorsCollaborators

W. Kalt W. Kalt AgriAgri, Canada, Canada

M. Smith, PhD, CWRU,M. Smith, PhD, CWRU,Cleveland, OHCleveland, OH

G. G. CasadesusCasadesus, CWRU, , CWRU, Cleveland, OHCleveland, OH

B. Rabin, UMBCB. Rabin, UMBC

D. Malin Univ. Houston, TXD. Malin Univ. Houston, TX

R. Martin Burke Med. Res, R. Martin Burke Med. Res,

C. AndresC. Andres--LacuevaLacueva, Univ. of Barcelona, , Univ. of Barcelona, Spain Spain

D. Ingram, NIH/NIAD. Ingram, NIH/NIA

C. C. WolkowWolkow, NIH/NIA, NIH/NIA

M. Wilson, NIH/NIAM. Wilson, NIH/NIA

R. Prior, CNRC, USDAR. Prior, CNRC, USDA

M. M. TalanTalan, NIA, GRC, NIA, GRC

G. Brewer, UI Cham. UrbanaG. Brewer, UI Cham. Urbana