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Promoting Healthy Aging through Nutrigenomics: The Potential of the Traditional Okinawan Diet
Donald Craig Willcox1, Giovanni Scapagnini2, Bradley J. Willcox11Dept of Geriatric Medicine, University of Hawaii; 2Institute of Neurological
Sciences, Italian National Research Council, Catania, Italy
TODAY`S MENU
Breakfast: Review nutrigenomics in relation to healthy aging
Lunch: Introduce relevant findings from our ongoing research
projects in Okinawa and Hawaii on healthy aging and longevity and highlight the connections with nutrigenomics
Dinner: Suggest possible nutritional interventional
approaches to modulate
gene expression based on
nutrigenomic properties of the traditional Okinawa Diet
The World`s Oldest PersonThe World`s Oldest Person……EVER !EVER ! 122 years at death122 years at death
Jeanne-Louise Calment of France 1875-1997
Age 20 years
Age 116 years
Projected Increases in Global Population by Age
Source: United Nations Department of Economic and Social Affairs, Population Division. World Population Prospects. The 2004 Revision. New York: United Nations, 2005.
PresenterPresentation NotesThe world's oldest population is the fastest growing
(Age adjusted mortality per 100,000 )Rank Location Life CHD Cancer Stroke All
Expectancy Causes1 Okinawa 81.2 18 97 35 3352 Japan 79.9 22 106 45 3643 Hong Kong 79.1 40 126 40 3934 Sweden 79.0 102 108 38 4358 Italy 78.3 55 135 49 45910 Greece 78.1 55 109 70 44918 USA 76.8 100 132 28 520
WHO Lives the Longest…and WHY ?(who has lowest risk for major killers)
Suzuki et al. Asia Pac J Clin Nutr 2001Suzuki et al. 2001
What is Nutrigenomics?
The study of how different foods can interact with particular genes to increase or decrease the risk of diseases such as type
2 diabetes, obesity, heart disease and some cancers
van Ommen B. (2004) Nutrition 20:4-8.
Age‐related Disability & Disease and Lifelong Accumulation of Cell
Damage thru Genetic, Environment & Intrinsic (chance) Effects
Accumulation of Cellular Defects
Inflammation
Poor NutritionEnvironmentStress
Anti‐Inflammatory
Healthy
Nutrition
HealthyLifestyle
Random Molecular Damage
Kirkwood
T. (2005) Cell 120;437‐447
General Research Methods of OCSGeneral Research Methods of OCS
PopulationPopulation--based study based study
(900+ cases 1976(900+ cases 1976--
present)present)
CrossCross--sectional, longitudinal, casesectional, longitudinal, case--
controlcontrol
Age validation Age validation
Geriatric exam with PMH, SH, FH, Geriatric exam with PMH, SH, FH, health habits, anthropometry, ECGhealth habits, anthropometry, ECG
Family pedigreeFamily pedigree
ADLs, IADLs, ADLs, IADLs, psychosocial/cognitive testspsychosocial/cognitive tests
Blood drawBlood draw
The Hawaii Lifespan Studies I and II Defining the Healthy Aging Phenotype (I) NIAR01AG027060 and Genotype (II) 2NIAR01AG027060
POPULATION
8,006 middle‐aged American men of Japanese ancestry from the
Honolulu Heart Program, followed since 1965
> now over 1200 nonagenarians and centenarians
Hawaii LIFESPAN Study I AIMS
Improve “healthy aging”
phenotypes (better quantify)
Examine (1) environmental and (2) genetic correlates of healthy aging
and longevity using mainly regression analyses
Focus on insulin‐signaling pathway genes
Hawaii LIFESPAN Study II AIMS
Sequence the FOXO3 gene to find “the”
variant
Understand how the gene reduces mortality Better understand the “longevity mechanism”
Japanese‐
American
centenarian,
age 101 years
Interesting “Caloric Restriction (CR) Longevity” Phenotype in Older Okinawans - genetic or environmental?
Less (lifetime) chronic diseaseHigher physical/cognitive function Shorter statureLower BMILower blood sugarLower % T2DMHigher HDLLow cancer
(Willcox et al. Ann NY Acad Sci 2007)
PresenterPresentation NotesVs. Japanese and Americans of similar ageCR or genetics? Don’t know. Need to compare to other populations? Maybe bec isolated island pop with inbreeding congerate lgene no eveidence form GW study Both genetic and environmental things going on…what is more powerful? Some things changing, still shorter despite env change, could be genetic diffs,
Fontana L et al. Science 2010
Ames and Snell dwarf mice Growth hormone receptor KO mice IGF-1 receptor deficient mice Klotho overexpressing mice Fat Insulin Receptor KO (FIRKO) mice Insulin Receptor Substrate 1 KO mice Brain IRS-2 KO mice Ribosomal S6 protein kinase-1 KO mice p66shc KO mice Type 5 Adenylyl Cyclase KO mice Angiotensin II type 1 receptor KO mice Mice overexpressing catalase targeted to mitochondria
DownregulationInsulin/IGF-1
andmTOR
pathways=
Nutrient –sensingsignalling pathways
Caloric Restriction : Most Powerful AntiCaloric Restriction : Most Powerful Anti‐‐Aging InterventionAging Intervention Calorie Restriction (CR) Reduces Cardiovascular and Cancer MortaCalorie Restriction (CR) Reduces Cardiovascular and Cancer Mortality by 50% in Nonlity by 50% in Non‐‐human Primateshuman Primates
Colman et al. Science 2009
CRAd libitum
P = 0.03HR = 3.0
PresenterPresentation Notes27.6 yrs old = 80 yrs
CR mediated cancer prevention mechanisms
Longo and Fontana. Trends Pharmacol Sci 2010
Long‐term cardiometabolic effects of CR in humans
Prevention of obesity and type 2 diabetes
Improved lipid profilePowerful anti‐hypertensive and anti‐inflammatory effectsPrevention of atherosclerosisImprovement of left ventricular diastolic
function (younger hearts) Fontana et al. JAMA 2007Fontana et al. PNAS 2004
Gene Variants in the Insulin Signaling Pathway and Healthy Aging
Genes, Body Size and Longevity
yeast flies miceGene variants that result in lower blood sugar and blood insulin result in long-lived animals with increased resistance to oxidative stress……but what about human beings?
Gene Varient in Insulin Signaling Pathway Strongly Associated with Healthy Aging and Longevity
(Willcox et al. Proc Nat Acad Sci 2008)
Lower prevalence of cancer, CVD, better self- reported health, and higher physical and cognitive function, despite significantly older ages than controls. Greater insulin sensitivity and this was associated with homozygosity for the FOXO3A GG genotype.
“The FOXO Factors”are Master Regulators
An important downstream mechanism whereby FOXO3A may influence human aging is through modification of oxidative stress. In C. elegans, DAF-16 increases the expression of manganese superoxide dismutase (SOD2), which converts superoxide to less damaging hydrogen peroxide and is a potent endogenous protector against free radicals.
Tofu with Fish Lean Meat DishesRice with Vegetables
What do the Okinawan Elders Eat?
Bitter Melon with Tofu Nigana Greens Mozuku Seaweed
Key Features of Traditional Okinawa Diet
1) Low Caloric Density (plant‐based, low fat, moderate protein from soy, fish, lean meats)2) High Nutrient Density (Vitamins A,C, E,
potassium, magnesium, folate, and healthy oils)3) Phyto‐nutrient Rich (anti‐oxidants, polyphenols, flavonoids, carotenoids mostly from green leafy
and yellow root vegetables)4) Low in Glycemic Load (high quality carbohydrates from staple sweet potato)5) Anti‐inflammatory (CR, antioxidants,
polyphenols, flavonoids, omega 3 fatty acids、 curcumins)
Willcox et al (2009) J American College Nutrition 28, (4), 500–516
Okinawan Sweet Potatoes
Kano et al. Antioxidative activity of anthocyanins from purple sweet potato,Ipomoera batatas cultivar Ayamurasaki. Biosci Biotechnol Biochem 69:979–988, 2005.
Sweet Potato: The Staple of the Traditional Okinawa Diet
Willcox et al Journal of American College of Nutrition 2009
USDA: Americans lack sufficient amounts of dietary fiber, calcium, magnesium, potassium, and the antioxidant vitamins A (as carotenoids), C and E.
Gl of Satsuma Imo (Sweet Potato) and Other Potatoes
Willcox et al Journal of American College of Nutrition 2009
http://www.nutritiondata.com/facts/vegetables‐and‐vegetable‐products/2667/2
Okinawa Sweet Potato is highly anti-inflammatory !
The sweet potato truck comes a`calling…..
CURCUMIN : A STRONG ANTI-OXIDANT AND ANTI-INFLAMMATORY
Mice Fed Curcumin and Polyphenols Live Longer Kitani et al (2004) Ann NY Acad Sci 1019:424‐426
Average life span in TC fed mice* was 11.7% longer than in control mice. The 10% longest survival also significantly greater and increase in average life expecancy after 24 months of age was 126%.In mice fed polyphenols average life span increased 6.4% and increase in average life expctancy after 24 months was 72.6%.
* TC: tetrahydrocurcumin * Green tea polyphenols
Soy flavonoids have antioxidant- like effects and hormetic properties and are potent activators of gene expression in FOXO3. Isoflavones, the type of flavonoids most common in soy, also regulate the Akt/FOXO3a/GSK-3beta/AR signaling network in prostate cancer cells. Specifically, they inhibit cell proliferation and foster apoptosis suggestingthat isoflavones might prove useful for the prevention and/or treatment of prostatecancer (Li et al. 2008. Biol Chem. 283, 27707-16.)
Astaxanthin is a xanthophyll carotenoid present in microalgae, fungi, complex plants, seafood (salmon, shrimp, krill). A strong antioxidant with anti-
inflammatory properties with potential as a therapeutic agent in
atherosclerotic cardiovascular disease. There is evidence of a reduction in oxidative stress and inflammation in a small number of clinical studies. This pigment is also commercially produced from the microalga Haematococcus pluvialis, the richest known natural source. (picture is Big Island, Hawaii) Fassett and Coombes Marine Drugs.
2011;
9: 447–465.
Recent evidence suggests that astaxanthin has promise for modulating aging through activation of the insulin signaling pathway and FOXO3 genein particular. Especially, the expression of genes encoding superoxide dismutases and catalases . AX likely protects the cell organelle mitochondria and nucleus of the nematode, resulting in a lifespan extension via Ins/IGF-1 signaling pathway.
Anti-oxidant Activity of Carotenoids
FOXO3a inhibits invasive phenotype of NF639 and rel/CK2-5839 cells
Belguise K et al. Cancer Res 2007;67:5763-5770
©2007 by American Association for Cancer Research
Activation of FOXO3a by the Green Tea PolyphenolEpigallocatechin-3-Gallate ( ECGC) Induces Estrogen Receptor α ExpressionReversing Invasive Phenotype of Breast Cancer Cells
PresenterPresentation NotesFOXO3a inhibits invasive phenotype of NF639 and rel/CK2-5839 cells. A, NF639 cells were infected with a retrovirus control (pBabe) or retrovirus expressing A3 FOXO3a (A3). Whole cell protein extracts were subjected to immunoblotting for FOXO3a, E-cadherin (E-cad), Snail, and β-actin, which showed equal protein loading. B, NF639 cells were infected with a retrovirus control (pBabe) or retrovirus expressing A3 FOXO3a and grown either in Matrigel or on plastic. Top, after 6 d, the colonies in Matrigel were photographed at a magnification of 50×. Representative fields are shown. Bottom, NF639 cells infected with control pBabe or pBabe expressing A3 FOXO3a were seeded at a density of 20,000 cells per well in 24-well cell culture dishes. After 3 d, both cultures reached confluence. C, NF639 cells were infected with pBabe-puro-A3 FOXO3a (A3) or pBabe-puro (pBabe) retrovirus. After 7 d of selection with puromycin, 5 × 105 cells were subjected to a migration assay for 6 h. OD410 nm values correspond to cells that migrated to the lower side of the filter and represent the mean of three determinations. D, rel/CK2-5839 cells were infected with pBabe-puro-A3 FOXO3a or pBabe-puro retrovirus. After 7 d of selection with puromycin, 5 × 105 cells were subjected to a migration assay for 6 h. OD410 nm values correspond to cells that migrated to the lower side of the filter and represent the mean of three determinations. Inset, whole cell protein extracts prepared from rel/CK2-5839 cells infected with control pBabe or pBabe expressing A3 FOXO3a were subjected to immunoblotting for Snail and β-actin.
Okinawa Traditional Dietary Intervention Study in Americans
Vacuum Packed Bento
Okinawa Diet Intervention Achieves “DASH*-like” Blood Pressure Reductions in Americans
70
80
90
100
110
120
130
0 2 3
M onth
Blood pressure(m
mHg)
S B P (A group)
S B P (B group)
D B P (A group)
D B P (B group)
A group intervention
B group intervention
1. SBP reduced 2.6 mm Hg (95% CI -4.3, -1.2. 2. DBP reduced 2.1mm Hg (95%CI -3.1 -1.0)
and 0.3mmHg (95%CI -2.1 0.6).
3. 24h-urinary sodium and body weight reduced (between-group differences ranged from p=0.032 to 0.0002).
Todoriki et al J Hypertension 2008
*Dietary Approaches to Stop Hypertension (DASH:
Most common physician prescribed diet to lower high blood pressure
in the U.S.
Try it !
Even in Very Late Life
(Nonagenarians) Survival is Longest in those with
Healthy Diet and
Good Genes (participants from Honolulu Heart Program)
HDI = Healthy Diet Index (ate healthy diet); FOXO3+ indicates prevalence of protective allele
Conclusions
Chronic low grade inflammation may be a major
determinant of ageing rate and longevity
Recent research has uncovered important “longevity
genes”
and pathways that regulate the aging process (ie. Foxo)
Nutritional approaches such as flavonoids, polyphenols,
omega 3 fatty acids, and calorie restriction are promising and further research is needed in dietary, cell‐based and
pharmacological strategies for healthy aging
The Okinawa diet contains many such compounds with
potentially powerful nutrigenomic
effects and research is underway in order to isolate the most promising
candidates (eg. Sweet potato extracts, curcumin, soy flavonoids, sanpin
and green tea, etc.) that will up‐
regulate the most promising target genes.
UshiUshi--sansan 102 Years Young and 102 Years Young and Still Still DigginDiggin’’ LifeLife
Mahalo
!
Domo Arigato! Domo Arigato!
Support & Financial Disclosure
The investigators retained full independence in the conduct of this
research and acknowledge the support from:
The John A. Hartford Center of Excellence in Geriatrics, Dep’t of
Geriatric Medicine, John A. Burns School of Medicine, University
of
Hawaii
Kuakini
Medical Center
US National Institute on Aging
US National Heart, Lung, and Blood Institute
Japan Society for the Promotion of Science
Special thanks to Dr. Makoto Suzuki (PI of Okinawa Centenarian Study)
and Dr. Hidemi
Todoriki
(PI of Chample
Study). For more information
on the Okinawa centenarian Study see www.okicent.org
Dr. Donald CraigWillcox
is Head of the Scientific Advisory Board for
Koruchem
Therapeutix, an evidence‐based pharmaceutical and
nutra/cosmaceutical
company
(www.koruchemtl.com)
http://www.koruchemtl.com/
Slide Number 1Today`s Menu Slide Number 3The World`s Oldest Person…EVER !� 122 years at death Slide Number 5Slide Number 6Slide Number 7 What is Nutrigenomics?Slide Number 9 Age-related Disability & Disease and Lifelong Accumulation of Cell � Damage thru Genetic, Environment & Intrinsic (chance) Effects�Slide Number 11Slide Number 12�The Hawaii Lifespan Studies I and II�Defining the Healthy Aging Phenotype (I) NIAR01AG027060 and Genotype (II) 2NIAR01AG027060Interesting “Caloric Restriction (CR) Longevity” Phenotype in Older Okinawans - genetic or environmental? Slide Number 15Slide Number 16Slide Number 17Slide Number 18Caloric Restriction : Most Powerful Anti-Aging Intervention�Calorie Restriction (CR) Reduces Cardiovascular and Cancer Mortality by 50% in Non-human Primates CR mediated cancer prevention mechanismsLong-term cardiometabolic effects �of CR in humansSlide Number 22Slide Number 23Slide Number 24 “The FOXO Factors”are Master Regulators�Slide Number 26Slide Number 27Key Features of Traditional Okinawa DietSlide Number 29 Sweet Potato: The Staple of the Traditional Okinawa Diet Gl of Satsuma Imo (Sweet Potato) and Other PotatoesSlide Number 32Slide Number 33Slide Number 34Mice Fed Curcumin and Polyphenols Live Longer�Kitani et al (2004) Ann NY Acad Sci 1019:424-426Slide Number 36Slide Number 37Slide Number 38Slide Number 39Slide Number 40Slide Number 41Okinawa Traditional Dietary Intervention Study in Americans Vacuum Packed Bento� Okinawa Diet Intervention Achieves “DASH*-like” � Blood Pressure Reductions in Americans Slide Number 45� ���� Even in Very Late Life (Nonagenarians) Survival is Longest in those with � Healthy Diet and Good Genes (participants from Honolulu Heart Program) � ConclusionsSlide Number 48 Support & Financial Disclosure�