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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
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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
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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
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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
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(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
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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.
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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
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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
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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
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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,
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Fontana L et al. Science 2010
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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
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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
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CR mediated cancer prevention mechanisms
Longo and Fontana. Trends Pharmacol Sci 2010
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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
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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?
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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.
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“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.
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Tofu with Fish Lean Meat DishesRice with Vegetables
What do the Okinawan Elders Eat?
Bitter Melon with Tofu Nigana Greens Mozuku Seaweed
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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
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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.
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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.
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Gl of Satsuma Imo (Sweet Potato) and Other Potatoes
Willcox et al Journal of American College of Nutrition 2009
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http://www.nutritiondata.com/facts/vegetables‐and‐vegetable‐products/2667/2
Okinawa Sweet Potato is highly anti-inflammatory !
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The sweet potato truck comes a`calling…..
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CURCUMIN : A STRONG ANTI-OXIDANT AND ANTI-INFLAMMATORY
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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
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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.)
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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.
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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.
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Anti-oxidant Activity of Carotenoids
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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.
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Okinawa Traditional Dietary Intervention
Study in Americans
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Vacuum Packed Bento
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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.
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Try it !
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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
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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.
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UshiUshi--sansan 102 Years Young and 102 Years Young and Still
Still DigginDiggin’’ LifeLife
Mahalo
!
Domo Arigato! Domo Arigato!
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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�