Healthy Aging: Antioxidants, Adaptogens & Cognition

Karen Butler Michael Altman, CN, RH (AHG) Kieron Edwards, Ph.D. Senior Editor Herbalist Nutritionist Chief Scientific Officer Informa Markets Anthocyanins International LLC Sibelius Natural Products (SeattleCancerCareAlternatives.com)

David Heber, M.D., Ph.D., FACP, FASN Katie Stage, N.D., RH (AHG) Professor Emeritus and Founding Director, Therapeutics Division Director UCLA Center for Associate Professor, Southwest Human Nutrition College of Naturopathic Medicine (SCNM) Booth #5310 Towards healthy aging

Kieron Edwards PhD MBA www.sibeliusnaturalproducts.com OCTOBER 2019 1 Talk outline Booth #5310

. The trends and challenges of aging . What occurs during aging? . Theories, effects, and pathways of aging . Supporting healthy aging

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

3 The trends and challenges of aging Booth #5310

4 What is aging? Booth #5310

. 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)

5 Age-related changes to health Booth #5310

. 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

6 Living longer and better? Booth #5310

. 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) 7 An aging global population Booth #5310

. 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) An aging global population Booth #5310

. 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

9 Aging: A challenge and an opportunity Booth #5310

. 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

10 What occurs during aging? Booth #5310

(Lopez-Otin et al., “The Hallmarks of Aging”, Cell 2013 11 Programmed, error, or both? Booth #5310

. 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

12 Mitochondrial dysfunction and ROS Booth #5310

. 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) Build up of un-degradable molecules Booth #5310

. 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) Senescence Booth #5310

. Stable arrest of the cell cycle SASP . Linked to telomere shortening, DNA damage, Inflammation 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

15 (Image credit: Stroo et al., Frontiers in Neuroscience, 2017) Core pathways of aging Booth #5310

. 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

16 Core pathways of aging Booth #5310

. 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

(Barzila et al., Perspectives in Diabetes, 2012) 17 Supporting healthy aging Booth #5310

18 Healthy aging Booth #5310

. 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

19 Clues from other species Booth #5310

. 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

20 Clues from long-lived humans Booth #5310

. Role for genetics in longevity, but it is still a plastic trait . Long-lived people in “Blue-zones” show some consistent

behaviours Sardinia, Italy Ikaria, Greece . Diet • Moderate calorie intake/intermittent fasting • Rich in plant-based foods Loma Linda, CA • Moderate alcohol . Physical activity Nicoya, Costa Rica . Sleep . Mood Okinawa, Japan • Social interaction, sense of purpose, avoidance of chronic stress...

21 Supporting healthy aging Booth #5310

. 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

22 Summary Booth #5310

. 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

23 Going beyond slowing down? Booth #5310

. 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

24 Booth #5310

25 Booth #5310 A Nutraceutical Platform Technology for Health THANK YOU Sibelius [email protected]

Kieron Edwards PhD MBA www.sibeliusnaturalproducts.com 26 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 DISCLOSURES

McCormick Science Institute – Honoraria and Travel Herbalife Nutrition Institute – Honoraria and Travel POM Wonderful – Research Awards Inflammaging

Information Classification: General 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+).

Information Classification: General Dunedin Study A longitudinal investigation of health and behavior in a complete birth cohort. Study members (N=1,037) were all born between April 1972 and March 1973 in Dunedin, New Zealand (NZ). Assessments were carried out at birth and ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, 32, and, most recently, 38 years, when 95% of the 1,007 study members still alive took part.

Belsky et al., 2015 (PNAS) 5 Information Classification: General Successful Aging Begins While We’re Young

“1” indicates a cohort member who experienced one year of physiological change per chronological year (the cohort average) “0” indicates a cohort member “2” indicates a cohort whose physiology member aging at a rate remained of two years of unchanged between physiological change ages 26 and 38. per chronological year, twice as fast as the population norm.

Distribution of Pace of Aging in the Dunedin Cohort. Pace of Aging is denominated in years of physiological change per chronological year.

Belsky et al., 2015 (PNAS) 6 Information Classification: General Inflammation Markers Increase with Age

Journals of Gerontology: Biological Sciences, 2019, Vol. 74, No. 3 Information Classification: General Oxidant Stress & Aging

Information Classification: General Aging Disease

Age Grey Zone Disease Vascular Stiffness High Blood Pressure Atherosclerosis Bone Loss Osteopenia Osteoporosis Decline in Glucose Pre-Diabetes Diabetes Tolerance Alzheimer’s and other Loss of Neurons MCI Neurodegenerative Diseases Loss of Visual Accommodation Presbyopia Cataract (Lens stiffening)

Pittsburg Mind Body Center Information Classification: General A Colorful Diet

Information Classification: General Polyphenols

• Polyphenols are a large and heterogeneous group of antioxidant phytochemicals containing phenol rings. • Several hundred different polyphenols are found in plant-based foods including broccoli, onion and cabbage, fruits, legumes, cereals, plant-derived beverages and chocolate. • Fruits such as grapes, pears, apples, cherries and various berries contain up to 200–300 mg polyphenols per 100 g fresh weight. • Approximately 100 mg of polyphenols are found in a cup of coffee or tea or a glass of red wine.

Information Classification: General Polyphenols

Information Classification: General Food Sources of 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.

Information Classification: General Tea Polyphenols

Information Classification: General Pomegranate Polyphenols

Information Classification: General A Cascade of Events

Metabolism Successful Polyphenols Prebiotic, & Cellular Effects Aging Postbiotic Effects (Life cycle)

Neuroprotection Oxidative Subclinical Stress Inflammation

Muscle Health Mitochondria Blood Flow Health Ellagitannins & • Urolithins A & B Micronutrients • Ellagic Acid • Indol-3-Proprionic Acid • Other Bioactives Skin Health

Information Classification: General Muscle Health

Information Classification: General How do Muscles Work?

We’ll come back to mitochondria in a bit…

Information Classification: General Mitochondria in Aging

Information Classification: General Mitochondria Autophagy

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

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

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

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 capacity 3. Extended lifespan

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

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

Confidential Information, Not for distribution Information Classification: General • ↓ DOMS, human (1-3) Urolithins Map • ↓ TNFα-induced muscle wasting, mouse (8) • ↑ Recovery from athletic muscle damage (7) Pomegranate’s Ellagitannins • ↑ Lifespan, C. Elegans (Li et al., TBD) (e.g., Punicalagin) Promotes Muscle Function • Antioxidant (3) Normal Weight > Over • Anti-inflammatory (3) Weight People (10) • Anti-Cancer (3) • ↑ Mitophagy , mouse (6) • ↑ Lifespan, C. Elegans (6) • ↑ Muscle function, grip & running, mouse (6) • ↓ TNFα-induced muscle wasting, mouse (8)

Over Weight > Normal Promotes Muscle Growth Weight People (10) • Antioxidant (3) • Anti-inflammatory (3) • Anti-Cancer (3) Associated with MetS (10) • ↑ Muscle growth, mouse (11)

1. Trombold et al., Med Sci Sports Exerc. 2010 Mar;42(3):493-8. 7. Ammar et al., PLoS One. 2016 Oct 20;11(10):e0160305. 2. Trombold et al., J Strength Cond Res. 2011 Jul;25(7):1782-8. 8. Redriguez et al., Mol Nutr Food Res. 2016 Nov 2. 3. Espin et al., eCAM. Volume 2013, Article ID 270418 9. Gonzalez-Sarrias et al., Mol Nutr Food Res. 2016 Nov 23. 4. Machin et al., Physiology Journal. Vol 2014, Article ID 271959 10. Selma et al., Food Funct. 2016 Apr;7(4):1769-74. 5. Tomas-Barberan et al., Mol. Nutr. Food Res. 2016, 00, 1–36 11. Rodriguez et al., J Cachexia Sarcopenia Muscle. 2017 Mar 1. 6. Ryu et al., Nat Med. 2016 Aug;22(8):879-88. 12. Tomas-Barberan et al., Mol Nutr Food Res. 2017 Jan;61(1).

Information Classification: General Neuroprotection

Information Classification: General Age-related changes in the brain

In order to recall a memory, you must activate a vast network of interconnecting brain cells called neurons (nerve cells). These brain cells deliver and permanently store messages along neural pathways, primarily in the cerebral cortex, the large, domed outer layer of the brain.

One brain cell communicates with another across a space called a synapse, by way of chemicals known as neurotransmitters. These neurotransmitters activate the receptors on the neighboring cell. Revisiting a memory strengthens the connections between brain cells that are responsible for maintaining that memory.

Information Classification: General Aging Brain and Memory

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

There are changes to the brain though loss of brain cells is minor until age 20. The brain is made of nerves which send out branches called axons. These axons are like wires that conduct electricity and they are coated with a fat called myelin. The length of these wires in the brain shorten 10% per decade after age 20.

However, inflammation is the likely culprit in serious loss of memory function. Information Classification: General Age is the Greatest Single Risk Factor for Memory Loss

50 45 Incidence 40 Prevalence 35 30 25 20 15 Rate (%) Rate 10 5 0 60 65 70 75 80 85 90 95 100 105

Age (years)

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

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.

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

Information Classification: General Information Classification: General 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. Information Classification: General Methods: fMRI Visual Memory Task

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

Original store façade Altered store (from encode phase) façade

Bookheimer et al., eCAM. 2013;2013:946298. Information Classification: General Results:

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

Bookheimer et al., eCAM. 2013;2013:946298. Information Classification: General Results:

3-D View

Bookheimer et al., eCAM. 2013;2013:946298. Information Classification: General Results: Pomegranate Juice Augments Memory and fMRI Activity in Middle-Aged & Older Adults with Mild Memory Complaints

1. PJ group performed Clinical Randomized Controlled Trial: n=28, 4 wks, 8oz PJ daily significantly better in memory testing compared to baseline p = 0.029 P = 0.022 (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). 35 Bookheimer et al., eCAM. 2013;2013:946298. Information Classification: General Results: Pomegranate Juice Augments Memory and fMRI Activity in Middle-Aged & Older Adults with Mild Memory Complaints

Clinical Randomized Controlled Trial: n=28, 4 wks, 8oz PJ daily Significant activation in visual The POM group (n=28) showed greater fMRI pathways (within-group means for activation than the placebo group in the 2 versus 1 contrast (p=0.05), located bilaterally both groups and at both time points ) in regions of the basal ganglia and thalamus.𝑡𝑡 including bilateral occipital cortex 𝑡𝑡 extending into temporal fusiform and parahippocampal gyrus, as well as activation in subcortical region across the 3 task conditions, consistent with visual memory processing and spatial navigation.

Bookheimer et al., eCAM. 2013;2013:946298. Information Classification: General 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

Information Classification: General Memory and Brain Amyloid and Tau Effects of a Bioavailable Form of Curcumin in Non-Demented Adults: A Double-Blind, Placebo-Controlled 18-Month Trial Gary 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 a bioavailable form of curcumin (Theracurmin® containing 90 mg of curcumin twice daily) 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 and cognitive benefits are associated with decreases in plaque and tangle accumulation in brain regions modulating mood and memory. • Curcumin’s cognitive benefits may stem from its anti-inflammatory and/or antiamyloid brain effects.

Information Classification: General Take Home Messages 1. 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 & Cognition

Herbal Extracts, Formulation and Clinical SOPs (Systemic Organ Protection) By: Michael C. Altman, RH (AHG), CN, MIIS Adjunct Professor Nutrition & Environmental Health Southern Oregon University SeattleCancerCareAlternatives.com Phyto-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://civileFcM3Vzt3 e7JU_rk4kAVvmQWt  Tannins: Oligomeric Proanthocyanidins from French Maritime Pine, Oak Bark, Hawthorn, Ginkgo, Grape Seed – blood pressure, edema, cancer, allergies 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, Adaptogens are non-toxic, normalize and Fungi function and can be used over the long term. They support various systems. Panax ginseng With ginseng, know your species and Withania somnifera (Ashwagandha) treatment. Some adaptogens like Oplopanax horridus (Devil’s Club) Aralia and Oplopanax have a Lepidium meyenii (Maca) respiratory affinity. Others like ginseng and Ganoderma are heart-centric. Aralia racemose (Spikenard) With mushrooms, know your substrate, Schisandra chinensis where and on what your raw material is Ganoderma (Reishi) grown, and how it’s extracted Cordyceps Swim tests, altitude, stress, endocrine and sexual enhancement Eleutherococcus (Siberian ginseng) Nootropics and Nervous System Support Nervines, Calm Stimulants, & Anxiolytics  Bacopa  Melissa (Lemon balm)  Herbs that nourish the nervous and  Avena (Milky oat) cardiovascular systems, support  Piper methysticum (Kava) them with their phytochemical and mineral contributions and help with  Centella (Gotu Kola) symptom control: anxiety, tics,  Paeonia lactiflora (White Peony) tremors, senescence  Cross reference adaptogens such as Schisandra and Ashwagandha  Rosmarinus (Terpenes)  Crocus sativus (Saffron)  Scutellaria lateriflora (don’t confuse) with Baical Skullcap root  Cannabis KATIE STAGE, ND RH (AHG) HEALTHY AGING: ANTIOXIDANTS, ADAPTOGENS & COGNITION OCTOBER 16, 2019 OPTIMIZING AN AGING BRAIN COGNITIVE ENHANCEMENT OBJECTIVES

• 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 AGING AND COGNITIVE DECLINE

• 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) AGING BRAIN

• Antioxidants

• Perfusion

• Acetylcholine (ACh)

• Inflammation

• Brain-derived neurotrophic factor (BDNF) ANTIOXIDANTS

• 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 OPTIMIZING ACETYLCHOLINE (ACH)

• 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)

Icon made by Surang from www.flaticon.com PERFUSION

• 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)

Icon made by Smashicons from www.flaticon.com DECREASING INFLAMMATION

• 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)

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

• 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 GINGKO BILOBA

• 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 GINGKO BILOBA

• 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 BACOPA MONNIERI

• 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} BACOPA MONNIERI

• 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 CENTELLA ASIATICA

• 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 CENTELLA ASIATICA

• 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) HUPERZIA SERRATA

• 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}} HUPERZINE 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) SALVIA OFFICINALIS, S. LAVANDULAEFOLIA

• 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) SALVIA

• Salvia officinalis reduced AChE and butyrylcholinesterase (BuChE); Saliva lavandulaefolia reduces 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 BERBERINE

• 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 BERBERINE

• 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 HERECIUM ERINACEUS

• 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 HERECIUM ERINACEUS

• 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 THE HAPPINESS FACTOR

• 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 Gingko X X X X X X

Bacopa X X X X X X

Gotu kola X X X X X

Huperzine A X X X X X

Sage X X X X X

Berberine X X X X X X

Lion’s mane X X X X X OPTIMIZING AN AGING BRAIN

• 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 Ric Scalzo Botanical Research Institute

Thank you!

Katie Stage, ND RH (AHG) = [email protected] REFERENCES 1

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