healthy aging: antioxidants, adaptogens & cognition...insulin igf-1 signalling (iis) pathway...

Healthy Aging: Antioxidants, Adaptogens & Cognition

Karen ButlerSenior Editor

Informa Markets

Michael Altman, CN, RH (AHG)Herbalist Nutritionist

Anthocyanins International LLC (SeattleCancerCareAlternatives.com)

Kieron Edwards, Ph.D.Chief Scientific Officer

Sibelius Natural Products

David Heber, M.D., Ph.D., FACP, FASNProfessor Emeritus and Founding

Director UCLA Center for Human Nutrition

Katie Stage, N.D., RH (AHG)Director, Therapeutics Division

Associate Professor, Southwest College of Naturopathic Medicine

(SCNM)

Booth #5310

OCTOBER 2019www.sibeliusnaturalproducts.com

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Towards healthy aging

Kieron Edwards PhD MBA

Booth #5310Talk outline The trends and challenges of aging What occurs during aging? Theories, effects, and pathways of aging

Supporting healthy aging

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Booth #5310Aging: The monster at the end of the book

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Booth #5310The trends and challenges of aging

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Booth #5310What is aging? Ageing results from the impact of the

accumulation of a wide variety of molecular and cellular damage over time. This leads to a gradual decrease in physical and mental capacity, a growing risk of disease, and ultimately, death. But these changes are neither linear nor consistent, and they are only loosely associated with a person’s age in years (WHO)

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Booth #5310Age-related changes to health Physical aging

Sensory loss, body composition changes, osteoarthritis Cognitive aging Immune aging

Immunosenecence, inflammation Cardiovascular health

CVD is still the leading cause of death in older adults Metabolic health Cancer

Second leading cause of death in older adults

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Booth #5310Living longer and better?

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Human lifespan is increasing Almost 2 years increase per decade

Age is a major risk-factor in many human diseases and conditions 62% of Americans over 65 have more than one

chronic condition (Ward et al., 2013)

Healthspan has not increased at the same rate

(Bellantuono et al., 2018)

Booth #5310An aging global population Global population over 60 years

1980 – 382 million 2017 – 962 million (over 80 137 million) 2050 – 2.1 billion (over 80 425 million)

Growth much faster in less developed countries

But still occurring in developed countries

8(Statistics from “World population ageing; 2017 highlights” report, United Nations)

Booth #5310An aging global population

Larger number of older adults but also increasing percentage By 2050 35% of European and 28%

of N. American populations will be over 60 (United Nations, 2017)

Projections in US have older adults (>65) outnumbering children (<18) by 2035

Great burdens on individuals and society Provision of social- and health-care

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Booth #5310Aging: A challenge and an opportunity

Higher percentage of older adults take supplements

Healthy aging supplements sales are growing Is the opportunity bigger?

Not just Baby Boomers Millenials taking greater interest

Awareness from caring for older relatives Concern for cognitive and physical decline Realisation of importance of lifestyle choices

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Booth #5310What occurs during aging?

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(Lopez-Otin et al., “The Hallmarks of Aging”, Cell 2013

Booth #5310Programmed, error, or both? Pre-programmed process Regulated by the neuronal, endocrine system, and

changes in gene expression over time Natural selection will act on longevity if it is beneficial to

fitness Accumulation of damage or errors over time Cumulative damage form intrinsic and extrinsic factors

cause the reduction in function of biological system

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Booth #5310Mitochondrial dysfunction and ROS Mitochondrial function declines with age

Reduced ATP production Increased leakage from electron transport

chain – increased ROS and damage to biomolecules (DNA, proteins, lipids...)

Free-radical theory of aging Gradual accumulation of damage by ROS

leads to cellular aging• Superoxide dismutase (SOD) proteins present

in all aerobic organisms• However, hormetic effects of ROS as well and

ROS important to cell signalling

13(Image credit: Stroo et al., Frontiers in Neuroscience, 2017)

Booth #5310Build up of un-degradable molecules Multiple mechanism lead to build up of

molecules Toxic by-products of normal metabolism e.g.

Lipofuscin “age-pigment” Mis-processed or mis-folded of proteins e.g.

Amyloid proteins Advanced glycation end products (AGEs)

Contributes to breakdown of intracellular processing and transport mechanisms e.g. autophagy and proteolysis

Intracellular and extracellular aggregates Tau aggregates or Amyloidβ plaques Atherosclerotic plaques

14(Image credit: Stroo et al., Frontiers in Neuroscience, 2017)

Booth #5310Senescence Stable arrest of the cell cycle

Linked to telomere shortening, DNA damage, mitogenic signals...

Senescent cells accumulate in aged tissues SASP: pro-inflammatory conditions may

contribute to aging Inflammation a major risk factor in many age-

related diseases Contributes to decline in stem cell

populations with age Reduced regenerative capacity Atrophy and immunosenecence

• e.g. thymus

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SASPInflammation

(Image credit: Stroo et al., Frontiers in Neuroscience, 2017)

Booth #5310Core pathways of aging Studies in model organisms have identified several key

pathways of aging conserved across species Insulin IGF-1 Signalling (IIS) pathway strongly conserved Together with its core targets FOXO and mTOR Principally related to glucose sensing Mediates DR/CR benefits

Decreased IIS results in lower rates of cell growth and metabolism and therefore lower rates of cellular damage

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Booth #5310Core pathways of aging Inter-connected aging network Nutrient sensing plays a core role

IIS – Glucose mTOR – amino acid concentrations AMPK – low energy status [AMP] Sirtuins – low energy status [NAD+]

Regulates balance of anabolism and catabolism

Pro-longevity treatments mimic low nutrient availability e.g. Rapamycin

17(Barzila et al., Perspectives in Diabetes, 2012)

Booth #5310Supporting healthy aging

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Booth #5310Healthy aging There is undeniably a strong role of accumulation of error and

damage over time in aging Some of these factors are intrinsic, but other drivers are

external e.g. Environmental damage and stresses

Can we slow down or even reverse this damage? Slow down the sand-timer

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Booth #5310Clues from other species What positive interventions to take? Calorie restriction has demonstrated increased longevity

across multiple species First demonstrated in rodents in the 1930s

Various treatments also show consistent effects across multiple species Rapamycin, Resveratrol, Curcumin... Act on these core pathways of aging

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Booth #5310Clues from long-lived humans Role for genetics in longevity, but it is still a plastic trait Long-lived people in “Blue-zones” show some consistent

behaviours Diet

• Moderate calorie intake/intermittent fasting• Rich in plant-based foods• Moderate alcohol

Physical activity Sleep Mood

• Social interaction, sense of purpose, avoidance of chronic stress...

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Loma Linda, CA

Nicoya, Costa Rica

Okinawa, Japan

Sardinia, Italy Ikaria, Greece

Booth #5310Supporting healthy aging Positive lifestyle interventions have the potential to increase

longevity and delay the onset of age-related pathologies Supplements can make a key contribution to this

• Mimic calorie-restriction without the down-sides Demonstrating benefits in humans poses a challenge Aging is not recognised as a disease How do you measure aging?

To date limited evidence of efficacy in humans beyond epidemiological studies

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Booth #5310Summary Aging poses a significant challenge to individuals and society Basic research has identified many of the hallmarks associated

with aging Slowing down the accumulation of age-related damage has

promise to delay the on-set of age-related pathologies Improve peoples healthspan

Lifestyle interventions, including supplements, have the potential to contribute to this

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Booth #5310Going beyond slowing down? Lifestyle interventions may slow down – or even reverse –

some forms of age-related damage Other elements will likely require medical interventions e.g. Senence, tissue atrophy, accumulation of AGEs lipofuscin etc.

Relevant technologies are being developed so it is conceivable that these could be tackled as well Gene and enzyme therapies, stem-cell therapies, immunotherapies

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Booth #5310

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Booth #5310

A Nutraceutical Platform Technology for Health

www.sibeliusnaturalproducts.com

THANK YOUSibelius

[email protected]

Kieron Edwards PhD MBA26

Booth #5310

NEW RESEARCH WITH ANTIOXIDANT INGREDIENTS

David Heber, MD, PhD, FACP, FASN Professor Emeritus of Medicine and Public Health

Founding Director, UCLA Center for Human Nutrition

DISCLOSURESMcCormick Science Institute – Honoraria and

TravelHerbalife Nutrition Institute – Honoraria and

TravelPOM Wonderful – Research Awards

Information Classification: General

Inflammaging


How Do You Measure Age?• Chronological age does not

correlate perfectly with functional age, i.e. two people may be of the same age, but differ in their mental and physical capacities.

• Each nation, government and non-government organization has different ways of classifying age.

• Divisions are sometimes made between the young old (65–74), the middle old (75–84) and the oldest old (85+).

http://upload.wikimedia.org/wikipedia/commons/5/5a/Sabaa_Nissan_Militiaman.jpg

http://upload.wikimedia.org/wikipedia/commons/5/5a/Sabaa_Nissan_Militiaman.jpg


Dunedin StudyA longitudinal investigation ofhealth and behavior in a completebirth cohort.

Study members (N=1,037) were allborn between April 1972 andMarch 1973 in Dunedin, NewZealand (NZ).

Assessments were carried out atbirth and ages 3, 5, 7, 9, 11, 13, 15,18, 21, 26, 32, and, most recently,38 years, when 95% of the 1,007study members still alive took part.

Belsky et al., 2015 (PNAS) 5


Distribution of Pace of Aging in the Dunedin Cohort. Pace of Aging is denominated in years of physiological

change per chronological year.

“1” indicates a cohort member who

experienced one year of physiological change per chronological year (the cohort average)

“2” indicates a cohort member aging at a rate

of two years of physiological change

per chronological year, twice as fast as the population norm.

“0” indicates a cohort member

whose physiology remained

unchanged between ages 26 and 38.

Successful Aging Begins While We’re Young

Belsky et al., 2015 (PNAS) 6


Journals of Gerontology: Biological Sciences, 2019, Vol. 74, No. 3

Inflammation Markers Increase with Age


Oxidant Stress & Aging


Aging Disease

Age Grey Zone DiseaseVascular Stiffness High Blood Pressure Atherosclerosis

Bone Loss Osteopenia OsteoporosisDecline in Glucose

Tolerance Pre-Diabetes Diabetes

Loss of Neurons MCIAlzheimer’s and other

Neurodegenerative Diseases

Loss of Visual Accommodation

(Lens stiffening)Presbyopia Cataract

Pittsburg Mind Body Center


A Colorful Diet


Polyphenols

• Polyphenols are a large and heterogeneous group ofantioxidant phytochemicals containing phenol rings.

• Several hundred different polyphenols are found inplant-based foods including broccoli, onion andcabbage, fruits, legumes, cereals, plant-derivedbeverages and chocolate.

• Fruits such as grapes, pears, apples, cherries and variousberries contain up to 200–300 mg polyphenols per 100 gfresh weight.

• Approximately 100 mg of polyphenols are found in acup of coffee or tea or a glass of red wine.


Polyphenols


• Rich colors like reds, purples or black indicate that plant foods are excellent sources of polyphenols.

Choose foods such as blueberries, pomegranates, red grapes, cranberries, and red or purple sweet potatoes.

• Blueberries as well as foods such as black rice, purple barley, black sorghum, and purple potatoes are sources of anthocyanins, as well as other polyphenols.

• The compound responsible for the color of turmeric, called curcumin, also happens to be a polyphenol.

Food Sources of Polyphenols


Tea Polyphenols


Pomegranate Polyphenols


A Cascade of Events

• Urolithins A & B

• Ellagic Acid

• Indol-3-Proprionic Acid

• Other Bioactives

Neuroprotection

Muscle Health

Skin Health

Oxidative Stress

Blood FlowMitochondria Health

Subclinical Inflammation

Ellagitannins & Micronutrients

Successful Aging

(Life cycle)Polyphenols

Metabolism Prebiotic, &

Postbiotic EffectsCellular Effects


Muscle Health


How do Muscles Work?

We’ll come back to mitochondria in a bit…


Mitochondria in Aging


Mitochondria Autophagy

Imai & Lu. Curr Opin Neurobiol. 2011 Dec; 21(6): 935–941.


Exercise

Sebastian et al., EMBO J. 2016 Aug 1;35(15):1677-93.


Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Ryu et al., Nat Med. 2016 Aug;22(8):879-88.

Confidential Information, Not for distribution

In C. elegans: 1. Prevented the accumulation of dysfunctional mitochondria with age 2. Prolonged normal activity during aging in C. elegans, including mobility and

pharyngeal pumping, while maintaining mitochondrial respiratory capacity3. Extended lifespan

Author’s Conclusion: Findings highlight the health benefits of urolithin A and its potential application in strategies to improve mitochondrial and muscle function.

In rodents:Improved exercise capacity in two different mouse models of age-related decline of muscle functionLikewise for young rats.

Identified urolithin A (UA) as a natural compound that induces mitophagy both in vitro and in vivo following oral consumption.


Urolithins MapPomegranate’s Ellagitannins

(e.g., Punicalagin)

• ↓ DOMS, human (1-3)• ↓ TNFα-induced muscle wasting, mouse (8)• ↑ Recovery from athletic muscle damage (7)• ↑ Lifespan, C. Elegans (Li et al., TBD)

• Antioxidant (3)• Anti-inflammatory (3)• Anti-Cancer (3)• ↑ Mitophagy , mouse (6)• ↑ Lifespan, C. Elegans (6)• ↑ Muscle function, grip & running, mouse (6)• ↓ TNFα-induced muscle wasting, mouse (8)

• Antioxidant (3)• Anti-inflammatory (3)• Anti-Cancer (3)• ↑ Muscle growth, mouse (11)

Promotes Muscle Growth

Promotes Muscle Function

Normal Weight > Over Weight People (10)

Over Weight > Normal Weight People (10)

Associated with MetS (10)

1. Trombold et al., Med Sci Sports Exerc. 2010 Mar;42(3):493-8. 2. Trombold et al., J Strength Cond Res. 2011 Jul;25(7):1782-8.3. Espin et al., eCAM. Volume 2013, Article ID 2704184. Machin et al., Physiology Journal. Vol 2014, Article ID 2719595. Tomas-Barberan et al., Mol. Nutr. Food Res. 2016, 00, 1–366. Ryu et al., Nat Med. 2016 Aug;22(8):879-88.

7. Ammar et al., PLoS One. 2016 Oct 20;11(10):e0160305.8. Redriguez et al., Mol Nutr Food Res. 2016 Nov 2. 9. Gonzalez-Sarrias et al., Mol Nutr Food Res. 2016 Nov 23. 10. Selma et al., Food Funct. 2016 Apr;7(4):1769-74.11. Rodriguez et al., J Cachexia Sarcopenia Muscle. 2017 Mar 1. 12. Tomas-Barberan et al., Mol Nutr Food Res. 2017 Jan;61(1).


Neuroprotection


Age-related changes in the brainIn order to recall a memory, you mustactivate a vast network of interconnectingbrain cells called neurons (nerve cells).These brain cells deliver and permanentlystore messages along neural pathways,primarily in the cerebral cortex, the large,domed outer layer of the brain.

One brain cell communicates with anotheracross a space called a synapse, by way ofchemicals known as neurotransmitters.These neurotransmitters activate thereceptors on the neighboring cell.Revisiting a memory strengthens theconnections between brain cells that areresponsible for maintaining that memory.


Aging Brain and Memory

There are changes to the brainthough loss of brain cells is minoruntil age 20. The brain is made ofnerves which send out branchescalled axons. These axons are likewires that conduct electricity andthey are coated with a fat calledmyelin. The length of these wiresin the brain shorten 10% perdecade after age 20.

A steady decline in brain functions are seen starting aboutage 30 especially in many types of memory with aging.

However, inflammation is the likely culprit in serious loss of memory function.


Age is the Greatest Single Risk Factor for Memory Loss

05

101520253035404550

60 65 70 75 80 85 90 95 100 105

IncidencePrevalence

Brayne C: Will we all dement if we live long enough? In: Sachdev PS, ed. The Aging Brain. Netherlands: Swets & Zeitlinger; 2003:243-257.

Rate

(%)

Age (years)


Research suggests that the consumption of polyphenol-rich foods and drinks (e.g., grape juice, blueberries, & cocoa) and spices including curcumin are associated with cognitive benefits.Polyphenols are thought to positively affect cognitive function by a variety of mechanisms, including:

1. Inhibiting neuro-inflammation 2. Inducing neurogenesis and synaptic plasticity.

Perspectives on Polyphenols.

Sarubbo et al., Neurosci Biobehav Rev. 2018 Jul;90:456-470.


Perspectives on Polyphenols.1. Improved verbal learning and reduced semantic

interference on memory tasks in older adults with mild cognitive impairment were reported after consuming concord grape juice daily for 12 & 16 wks.

Krikorian et al., British Journal of Nutrition (2010), 103, 730–734

2. Supplementation with blueberry concentrate improved brain perfusion and activation in brain areas associated with cognitive function in healthy older adults.

Bowtell et al., Appl Physiol Nutr Metab. 2017 Jul;42(7):773-779

3. Improved cerebral blood flow has been observed in humans after the consumption of cocoa flavonols.

Lamport et al., Psychopharmacology (Berl). 2015 Sep;232(17):3227-34


Methods: fMRI Visual Memory Task

Taxi-cab memory test• Taxi drives the subjects through a virtual environment, stopping

at stores along the way in several different imaginary towns• Later, subjects are tested on which stores they saw, where they

were located

Bookheimer et al., eCAM. 2013;2013:946298.


Example of Visual Memory Task…Which store did you see?

Original store façade (from encode phase)

Altered store façade

Methods: fMRI Visual Memory Task



Taxicab Visual Memory: Pomegranate Juice > placebo, time2 > time1

Results:



3-D View

Results:



Results: Pomegranate Juice Augments Memory and fMRI Activity in Middle-Aged & Older Adults with Mild Memory Complaints

1. PJ group performed significantly better in memory testing compared to baseline (alternating test forms; p=0.017)

2. PJ group recalled more items on consistent long-term retrieval compared to controls (p=0.022).

3. Memory scores were significantly greater in the PJ group on the total recall measure (p=0.029).

p = 0.029P = 0.022

Clinical Randomized Controlled Trial: n=28, 4 wks, 8oz PJ daily

35Bookheimer et al., eCAM. 2013;2013:946298.


Significant activation in visualpathways (within-group means forboth groups and at both time points)including bilateral occipital cortexextending into temporal fusiformand parahippocampal gyrus, aswell as activation in subcorticalregion across the 3 task conditions,consistent with visual memoryprocessing and spatial navigation.

The POM group (n=28) showed greater fMRIactivation than the placebo group in the 𝑡𝑡2versus 𝑡𝑡1 contrast (p=0.05), located bilaterallyin regions of the basal ganglia and thalamus.

Clinical Randomized Controlled Trial: n=28, 4 wks, 8oz PJ daily

Results: Pomegranate Juice Augments Memory and fMRI Activity in Middle-Aged & Older Adults with Mild Memory Complaints



Double-Blind Placebo-Controlled Study of the Memory Effects of Pomegranate Juice

in Middle-aged and Older Adults*Prabha Siddarth, Ph.D., Zhaoping Li, M.D., Ph.D., Karen J. Miller, Ph.D., Linda

M. Ercoli, Ph.D., David A. Merrill, M.D., Ph.D., Susanne M. Henning, Ph.D., David Heber, M.D., Ph.D., Gary W. Small, M.D.

*Oral Presentation at American Association of Geriatric Psychiatry (March, 2019). Manuscript accepted for publication by the American Journal of Clinical Nutrition


Memory and Brain Amyloid and Tau Effects of a Bioavailable Form of Curcuminin Non-Demented Adults: A Double-Blind, Placebo-Controlled 18-Month TrialGary W. Small, M.D., Prabha Siddarth, Ph.D., Zhaoping Li, M.D., Ph.D., Karen J. Miller, Ph.D., Linda Ercoli, Ph.D., Natacha D. Emerson, M.A.,Jacqueline Martinez, M.B.A., M.S., Koon-Pong Wong, Ph.D., Jie Liu, Ph.D., David A. Merrill, M.D., Ph.D., Stephen T. Chen, M.D., Susanne M. Henning, Ph.D., R.D.,Nagichettiar Satyamurthy, Ph.D., Sung-Cheng Huang, D.Sc., David Heber, M.D., Ph.D., Jorge R. Barrio, Ph.D.Objective:

Highlights• This is the first long-term (18 months) double-blind, placebo controlled trial of abioavailable form of curcumin (Theracurmin® containing 90 mg of curcumin twicedaily) in non-demented adults.• We found that daily oral Theracurmin led to significant memory and attention benefits.• FDDNP-PET scans performed pre- and post-treatment suggested that behavioral andcognitive benefits are associated with decreases in plaque and tangle accumulationin brain regions modulating mood and memory.• Curcumin’s cognitive benefits may stem from its anti-inflammatory and/or antiamyloidbrain effects.

Take Home Messages1. Polyphenol antioxidants appear to be key to unlocking the

mystery of “inflammaging”. Polyphenols’ ability to combat oxidative stress, facilitate proper blood flow, and modulate inflammatory pathways is the basis for their health benefits.

2. Research suggests that polyphenols may support healthy muscle function, which is important to aging adults who are losing strength.

3. Research suggests that polyphenols may support increased brain activity and improvements in verbal memory and learning tasks in adults with age-associated mild memory complaints.

Healthy Aging: Antioxidants, Adaptogens & CognitionHerbal Extracts, Formulation and Clinical SOPs (Systemic Organ Protection)By: Michael C. Altman, RH (AHG), CN, MIISAdjunct Professor Nutrition & Environmental Health Southern Oregon UniversitySeattleCancerCareAlternatives.comPhyto-Formulation & Wellness Protocol Consultant

Antioxidants – Clinical Clout Flavonoids: Anthocyanins include pigmented compounds with abundant

research backing and long term use. As formulators we can include sustainably cultivated sources such as Haskap/Honeyberry (Lonicera caerulea), Acai and Black Currants, rather than exclusively wild harvested berries. Synthesizing these compounds? Key Anthos: C3G and D3G

The Bee’s Knees: Propolis and Bee Specialties https://civileats.https://civileats.com/2019/09/12/in-rural-appalachia-beekeeping-offers-a-new-path-for-coal-miners/?fbclid=IwAR0w9oq21RFtQqwZBN-TN_Qx-RBn4Tyy-FcM3Vzt3e7JU_rk4kAVvmQWt9AFcM3Vzt3e7U_rk4kAVvmQs://civileFcM3Vzt3e7JU_rk4kAVvmQWt

Tannins: Oligomeric Proanthocyanidins from French Maritime Pine, Oak Bark, Hawthorn, Ginkgo, Grape Seed – blood pressure, edema, cancer, allergies

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Specialty Cardiovascular Ingredients

Hippophae rhamnoides, Sea Buckthorn (Hippo phaos) Shining horse

Angelica keiskei (Ashitaba chalcone)

Allium sativum (Aged black garlic extract)

Nattokinase (from Glycine max) Soy based enzyme

Anthocyanins extracts

Novel TCM Herbs (Salvia miltiorrhiza aka Dan Shen, Red Sage Root) Tanshinones for neurogeneration and cardiovascular support

How do we improve lipids, reduce inflammation, improve vessel elasticity, and reduce resistance to healthy blood flow?

Adaptogens – Upregulating Survival Potential and Healthy Active Aging Find your Roots, Berries, Shoots,

and Fungi

Panax ginseng

Withania somnifera (Ashwagandha)

Oplopanax horridus (Devil’s Club)

Lepidium meyenii (Maca)

Aralia racemose (Spikenard)

Schisandra chinensis

Ganoderma (Reishi)

Cordyceps

Eleutherococcus (Siberian ginseng)

Adaptogens are non-toxic, normalize function and can be used over the long term. They support various systems.

With ginseng, know your species and treatment. Some adaptogens like Aralia and Oplopanax have a respiratory affinity. Others like ginseng and Ganoderma are heart-centric.

With mushrooms, know your substrate, where and on what your raw material is grown, and how it’s extracted

Swim tests, altitude, stress, endocrine and sexual enhancement

Nootropics and Nervous System SupportNervines, Calm Stimulants, & Anxiolytics Bacopa

Melissa (Lemon balm)

Avena (Milky oat)

Piper methysticum (Kava)

Centella (Gotu Kola)

Paeonia lactiflora (White Peony)

Cross reference adaptogens such as Schisandra and Ashwagandha

Rosmarinus (Terpenes)

Crocus sativus (Saffron)

Scutellaria lateriflora (don’t confuse) with Baical Skullcap root

Cannabis

Herbs that nourish the nervous and cardiovascular systems, support them with their phytochemical and mineral contributions and help with symptom control: anxiety, tics, tremors, senescence

H E A L T H Y A G I N G : A N T I O X I D A N T S , A D A P T O G E N S & C O G N I T I O N

O C T O B E R 1 6 , 2 0 1 9

K A T I E S T A G E , N D R H ( A H G )

C O G N I T I V E E N H A N C E M E N TO P T I M I Z I N G A N A G I N G B R A I N

O B J E C T I V E S

• Discover the leading theories on optimizing cognitive function

• Explore herbal therapies that support each mechanism of cognitive enhancement

• Understand concepts in formulating for maximum effect

A G I N G A N D C O G N I T I V E D E C L I N E

• Cognitive deficits are the most common consequences of the aging process (Budni, 2015)

• Much of the scientific research on cognition is centered around understanding Alzheimer’s disease and the resulting cognitive dysfunction

• Accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs)

• No strict correlation between the number of plaques and cognitive decline

• NFTs result from hyperphosphorylation of tau, a microtubule-associated protein.

• NFTs decrease neuronal function and do correlate with cognitive decline (Kinney, 2018)

• Chronic inflammatory changes trigger neurotoxins, further exacerbating Aβ and tau/NFTs (Kinney, 2018)

A G I N G B R A I N

• Antioxidants

• Perfusion

• Acetylcholine (ACh)

• Inflammation

• Brain-derived neurotrophic factor (BDNF)

A N T I O X I D A N T S

• Neurons are at high risk of oxidative damage due to high oxygen consumption and energy production

• Oxidative stress is implicated in cognitive decline and neurodegenerative disease

• Unclear whether this is a cause or consequence

• Those with ApoE genotype show higher oxidative damage than others, even before disease has manifested (Wojsiat, 2018)

• Oxidative stress damages amyloid plaques formed from beta-amyloids (Aβ) (Lokanathan, 2016), which stimulates more oxidative stress (Wojsiat, 2018)

• Clinical data limited; antioxidant intervention must to be able to cross the BBB (Teixeira, 2013)

• Antioxidant (beta carotene, vitamin C, and vitamin E) rich diet associated with lower risk of AD dementia (Wojsiat, 2018)

Icon made by Pixel Perfect from www.flaticon.com

O P T I M I Z I N G A C E T Y L C H O L I N E ( A C H )

• Acetylcholine (ACh) is used widely in the nervous system

• Attention, cognition, stress response, wakefulness, sleep, and in processing sensory information (Ferreira, 2016)

• Decline in cholinergic neurons / cholinergic transmission is a leading hypothesis for development of Alzheimer’s disease (Lokanathan, 2016)

• Pharmaceutical treatments for dementia are mostly aimed at optimizing ACh

• Increasing synthesis and up regulation of ACh

• Using AChE or butyrylcholinesterase (BuChE) inhibitors to slow breakdown of ACh

• Donepezil, rivastigmine, galantamine (Ferreira-Vieira, 2016)

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P E R F U S I O N

• Neurons are particularly sensitive to decreased blood perfusion

• Clinically, those with Alzheimer’s do show impaired perfusion to the brain (Toda, 2012)

• Decreased perfusion inhibits removal of Aβ; Aβ decreases NO availability and in turn decreases perfusion to the brain

• Decreased NO and endothelial dysfunction seen in conditions with higher risk of Alzheimer’s: age and cardiometabolic diseases

• AChE inhibitors (Donepezil) improve brain perfusion along with effect on ACh (Toda, 2012)

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D E C R E A S I N G I N F L A M M A T I O N

• Neuroinflammation is implicated in many neurological disorders including Alzheimer’s, PD, TBI, ALS, MS (Kinney, 2018)

• Chronically activated brain macrophages (microglia) and other immune cells release pro-inflammatory and toxic products

• Exacerbates both amyloid and tau pathology (Kinney, 2018)

• Chronic inflammation also seen in conditions which increase risk for Alzheimer’s including age, CVD, TBI, and diabetes (Kinney, 2018)

• Neuroinflammation is also seen in memory deficit due to chronic stress (Ar Rochmah, 2019)

GerryShaw [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)]Icon made by Freepik from www.flaticon.com

E N H A N C I N G B R A I N D E R I V E D N E U R O T R O P H I C F A C T O R ( B D N F )

• BDNF expression is modified by stressors; decreased expression contributes to depression, Alzheimer’s, Parkinson’s, epilepsy (Budni, 2015) and cognitive impairment (Qin, 2016)

• BDNF is a mediator of neuroplasticity

• Protects against the effects of chronic stress (Ar Rochmah, 2019)

• Protective against future occurrence of dementia (Weinstein, 2014)

• Because it is induced by exercise and reduced caloric intake, it is thought to mediate the association between healthy lifestyle and successful aging (Weinstein, 2014).

Icon made by DinosoftLabs from www.flaticon.com

G I N G K O B I L O B A

• Gingko, Maidenhair tree

• Leaf

• EGb 761® standardized extract

• 24% Flavonol glycosides, 6% terpene lactones (ginkgolides, bilobalide), < 5 ppm ginkgolic acids

• Available by Rx in Europe (Nash, 2015)

• Also used for tinnitus, headaches/migraines, as a cardiovascular tonic

G I N G K O B I L O B A

• Increases microcirculation to the brain

• Supports glucose levels and ATP utilization (Silberstein, 2011)

• Inhibiting the aggregation and toxicity of Aβ protein (Gauthier, 2014)

• Enhancing neuroplasticity and neuroprotection (Zhang, 2016)

• Improves outcomes in cerebrovascular disease (Gauthier, 2014)

• Increases dopamine levels in prefrontal cortex (Gauthier, 2014)

• Dose dependent* use increases working memory (Silberstein, 2011), cognition, neuropsychiatric symptoms, and daily activities (Zhang, 2016)

• Ginkgo flavonols for 4 months increased BDNF (Sangiovanni, 2017)

• Dose: 120-600mg (240mg) a day - safe; ensure standardized extract & authenticity

B A C O P A M O N N I E R I

• Brahmi, water hyssop

• Whole plant (areal)

• Triterpenoid saponins (bacosides), alkaloids (brahmine, nicotine), saponins (bacopasides)

• Standardized extract 25% bacoside A or 55% combined bacosides

• Medhya-rasayana (memory enhancer), hepatoprotective, anxiolytic*, mast cell stabilizer, anti-nociceptive (Sangiovanni, 2017)

{subst:User:Multichill/Starr|subst=subst:|URI=070815-8055|Species=Bacopa monnieri|Description=flowers|Location=Kanaha Beach|Island=Maui|Date=15-08-2007}

B A C O P A M O N N I E R I

• Potent anti-oxidant that crosses BBB

• Protective against environmental neurotoxins (Sangiovanni, 2017)

• Increases cerebral blood flow

• Inhibition of AChE and production of ACh

• β-amyloid reduction and monoamine potentiation (Aguiar, 2013)

• Clinical enhancement of memory acquisition, retention, attention, and memory processing - even in those without cognitive decline (Aguiar, 2013)

• Chronic and moderate use (200-400 mg a day) nourishes neurons; results best after 3 months administration (Aguiar, 2013)

• Generally very safe; mild GI upset in some; caution in hyperthyroidism

C E N T E L L A A S I A T I C A

• Gotu kola, Indian pennywort, Brahmi, Hydrocotyle asiatica

• Whole plant (leaves*)

• Triterpene saponins (asiatic acid, AA), madecassic acid and heterosides asiaticoside and madecassoside), minerals, flavonoids, EO (Orthan 2012, Lokanathan, 2016).

• ECa 233: 80% triterpenoid glycosides including asiaticoside (32.3%).

• TECA: 30% AA, 30% madecassic acid, 40% asiaticoside

• Medhya-rasayana, brain tonic and “miracle elixir of life”, wound healing/anti-fibrotic (Nagoor, 2018, Gohil, 2010), anxiolytic (Gohil, 2010)

By Funaki (Self-photographed) [Public domain], via Wikimedia Commons

C E N T E L L A A S I A T I C A

• Asiatic acid (AA) is a potent anti-oxidant (Grey, 2016) able to cross BBB

• Neuroprotective; attenuates neurotoxin-mediated cognitive decline (Nagoor, 2018)

• Asiaticosides, AA have anti-inflammatory activity in hippocampus (Nagoor, 2018)

• Does not seem to inhibit amyloid plaques directly (Krishnamurthy, 2009), but protects against against Aβ neurotoxicity (Nagoor, 2018) and may inhibit AChE (Lokanthan, 2016, (Orthan 2012

• Aasiaticocides prevent stress-related decline in BDNF (Ar Rochmah, 2019)

• Dose dependent (500mg -1,000mg/day) reduction in age-related cognitive decline after 2-6 months (Lokanathan, 2016)

• Generally safe, mild GI upset in some; possible anti-fertility effect (animals)

H U P E R Z I A S E R R A T A

• Chinese/toothed club moss, qian ceng ta, Lycopodium serratum

• Alkaloid (huperzine A)

• Licensed anti-AD drug in China (Qian, 2014)

• Endophytic fungal strain ES026 (Colletotrichum gloeosporioides) is also able to produce Huperzine A (Shu, 2014)

• Traditional uses: fever, swelling, pain, schizophrenia

Lycopodium serratum(Lycopodiaceae) Japanese name;Tougesiba Data;2006,08;kouyasan,Wakayama pref. Japan *Author;Keisotyo {{GFDL-self}}

H U P E R Z I N E A

• Reversibly and selectively inhibits AChE, preventing ACh breakdown (Ohba, 2015)

• More potent AChE inhibitor than Alzheimer’s medications donepezil, tacrine, and rivastigmine (Zhang, 2012)

• No effect on butyrylcholinesterase (BuChE) (Ohba, 2015)

• Reduced Aβ, deposityion of amyloid plaques, and hyperphosphorylated tau (Ohba, 2015)

• Four weeks of treatment upregulated BDNF, ameliorated behavioral changes and impaired neurological and cognitive function in post stroke depression rats (Du, 2017); decreased neuroinflammation after TBI (Mei, 2017)

• Dose 150-250 up to 400 mcg 2x/day (Zhang, 2012)

• Interactions with anticholinergic drugs; best avoided in pregnancy and lactation, SE: GI, tachycardia, fatigue, HTN, bradycardia, headache, muscle cramps (Zhang, 2013)

S A L V I A O F F I C I N A L I S , S . L A V A N D U L A E F O L I A

• Garden sage, Spanish sage

• Leaf

• Caffeic acid, rosmarinic acid, flavonoids, terpenes (α/β-thujone, camphor, 1,8-cineole, α-humulene, β-caryophyllene ), carnosic acid, ursolic acid, carnosol .

• Salvia lavandulaefolia does not contain α/β-thujone

• Carminitive, antimicrobial, antringent, anti-inflammatory (Lopresti, 2017)

S A L V I A

• Salvia officinalis reduced AChE and butyrylcholinesterase (BuChE); Saliva lavandulaefoliareduces AChE only (Lopresti, 2017)

• Potent anti-oxidant and anti-inflammatory properties that cross the BBB

• Rosemarinic acid restored hippocampal BDNF in chronically stressed rats (Lopresti, 2017)

• Caffeic acid attenuates the down-regulation of BDNF during stressful conditions (Lopresti, 2017)

• Improvements in word recall in healthy adults (Spanish sage volatile oil 50 µL 1-3x/day)

• Improved memory performance (333mg/day sage extract), also improved“alertness”, “contentedness”, “calmness” (sage leaf 150mg/day) (Tildesley, 2003)

• α/β-thujone inhibit sGABA-A receptor and may cause excitation and convulsions; EO of Salvia sp containing thujone should not be used internally

B E R B E R I N E

• Isoquinoline alkaloid found in the roots of Mahonia aquifolium, Berberis vulgaris, Coptis chinensis

• Also available as an isolated extract

• Poor bioavailability, chloride or sulphate salts are relatively more soluble and are used clinically (Fan, 2019)

• Anti-cancer, anti-microbial, anti-diabetic, hypolipidemic (Aski, 2017)

https://www.herbalremediesadvice.org/oregon-grape-herb.html

B E R B E R I N E

• Potent anti-inflammatory; redues cytokines TNF-α, COX-2, and IL-1β (Shal, 2018)

• Restores levels of CREB and BDNF (Shal, 2018)

• Protective against ischemic injury; antioxidant effect (Aski, 2017)

• Acts as AChE inhibitor; protective of cholinergic neurons in the hippocampus (Aski, 2017)

• Berberine (6 months) significantly improved cognitive deficits and insulin resistance in naturally aging rats (Yu, 2018)

• Protective effect on depression, anxiety, and stress response (Fan, 2019)

• Generally safe but CI in pregnancy and lactation; GI upset common, avoid combining with macrolide antibiotics. Dose 500mg- 2,000 mg/day

H E R E C I U M E R I N A C E U S

• Lion’s mane, Houtou mushroom, Yamabushitake

• Fruiting body, mycelium

• Hericenones (in fruiting body) and erinacines (in mycelium) (Li, 2018)

• Erinacine A-enriched mycelia

• Immune modulator, anti-depressant, hypoglycemic (I-Chen, 2019)

By Lebrac [CC BY-SA 2.5 (http://creativecommons.org/licenses/by-sa/2.5)], via Wikimedia Commons

H E R E C I U M E R I N A C E U S

• Hericenones (in fruiting body) and erinacines (in mycelium) increase nerve growth factor (NGF) in neurons, influencing neurogenesis and prolonging availability of ACh (Zhang, 2017)

• Oral administration of lion’s mane fruiting body improved mild cognitive impairment in 50- to 80-year-old Japanese patients (Li, 2018)

• Erinacines are neuroprotective

• Decreased cerebral Aβ plaque burden, prevention of plaque-associated microglia and astrocytes, enhanced nerve growth factor (NGF), and enhanced neurogenesis (Li, 2018)

• Erinacine A has protective against ischemic injury, Parkinson’s and Alzheimer’s (Chiu, 2018)

• Two weeks administration with mycelium activated the BDNF pathways and blocked NF-κB signals in mice (Li, 2018)

• Mycelium and fruiting body given for 2 months reversed the age-decline of recognition memory in frail mice (Ratto, 2018)

• Very safe, typical dose is 1g/day, effects seen in 30-60 days

T H E H A P P I N E S S F A C T O R

• Exposure to chronic and acute stress adversely affects cognition

• Depressive symptoms can be a prodrome to Alzheimer’s (Lopresti, 2017)

• Herbs that support mood and overall resilience support healthy cognition

• Also support people making healthy lifestyle choices such as eating well, regular exercise and meditation

G i n g k o X X X X X X

B a c o p a X X X X X X

G o t u k o l a X X X X X

H u p e r z i n e A X X X X X

S a g e X X X X X

B e r b e r i n e X X X X X X

L i o n ’ s m a n e X X X X X

O P T I M I Z I N G A N A G I N G B R A I N

• Herbal treatment shows considerable promise in vitro and in vivo, with a wider range of mechanisms than pharmaceuticals

• Safe and generally well tolerated for long periods of time

• Treatment 2-8 months+

• Treatments that optimize a healthy lifestyle also support cognition and healthy aging of the whole person

Katie Stage, ND RH (AHG) = [email protected]

Ric Scalzo Botanical Research Institute

Thank you!

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