Promoting Healthy Aging through Nutrigenomics: The Potential of the Traditional Okinawan Diet
Donald Craig Willcox1, Giovanni Scapagnini2, Bradley J. Willcox1 1Dept of Geriatric Medicine, University of Hawaii; 2Institute of Neurological Sciences, Italian National Research Council, Catania, Italy
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TheThe World`sWorld`s OldestOldest PersonPerson……EVEREVER !! 122122 yearsyears atat deathdeath 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. WHO Lives the Longest…and WHY ? (who has lowest risk for major killers)
(Age adjusted mortality per 100,000 ) Rank Location Life CHD Cancer Stroke All Expectancy Causes 1 Okinawa 81.2 18 97 35 335 2 Japan 79.9 22 106 45 364 3 Hong Kong 79.1 40 126 40 393 4 Sweden 79.0 102 108 38 435 8 Italy 78.3 55 135 49 459 10 Greece 78.1 55 109 70 449 18 USA 76.8 100 132 28 520
Suzuki et al. Asia Pac J Clin Nutr 2001 Suzuki 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
Inflammation Anti‐Inflammatory
Accumulation of Cellular Defects Healthy Healthy Nutrition Lifestyle Random Molecular Damage
Stress Environment Poor Nutrition
Kirkwood T. (2005) Cell 120;437‐447
GeneralGeneral ResearchResearch MethodsMethods ofof OCSOCS
Population-based study (900+ cases 1976- present) Cross-sectional, longitudinal, case- control
Age validation Geriatric exam with PMH, SH, FH, health habits, anthropometry, ECG
Family pedigree ADLs, IADLs, psychosocial/cognitive tests
Blood 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 Japanese‐ American centenarian, Hawaii LIFESPAN Study II AIMS age 101 years Sequence the FOXO3 gene to find “the” variant Understand how the gene reduces mortality
Better understand the “longevity mechanism” Interesting “Caloric Restriction (CR) Longevity” Phenotype in Older Okinawans - genetic or environmental?
Less (lifetime) chronic disease Higher physical/cognitive function Shorter stature Lower BMI Lower blood sugar Lower % T2DM Higher HDL Low cancer
(Willcox et al. Ann NY Acad Sci 2007)
Fontana L et al. Science 2010 Ames and Snell dwarf mice Growth hormone receptor KO mice IGF-1 receptor deficient mice Downregulation Klotho overexpressing mice Insulin/IGF-1 and Fat Insulin Receptor KO (FIRKO) mice mTOR Insulin Receptor Substrate 1 KO mice pathways Brain IRS-2 KO mice = Nutrient –sensing Ribosomal S6 protein kinase-1 KO mice signalling p66shc KO mice pathways Type 5 Adenylyl Cyclase KO mice Angiotensin II type 1 receptor KO mice Mice overexpressing catalase targeted to mitochondria CaloricCaloric RestrictionRestriction :: MostMost PowerfulPowerful AntiAnti‐‐AgingAging InterventionIntervention Calorie Restriction (CR) Reduces Cardiovascular and Cancer Mortality by 50% in Non‐human Primates
P = 0.03 HR = 3.0
Ad libitum CR
Colman et al. Science 2009 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 profile Powerful anti‐hypertensive and anti‐inflammatory effects Prevention of atherosclerosis Improvement of left ventricular diastolic Fontanafunction et al. PNAS 2004 (younger hearts) Fontana et al. JAMA 2007 Gene Variants in the Insulin Signaling Pathway and Healthy Aging Genes, Body Size and Longevity
yeast flies mice Gene 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.
What do the Okinawan Elders Eat?
Bitter Melon with Tofu Nigana Greens Mozuku Seaweed
Tofu with Fish Rice with Vegetables Lean Meat Dishes 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
USDA: Americans lack sufficient amounts of dietary fiber, calcium, magnesium, potassium, and the antioxidant vitamins A (as carotenoids), C and E.
Willcox et al Journal of American College of Nutrition 2009 Gl of Satsuma Imo (Sweet Potato) and Other Potatoes
Willcox et al Journal of American College of Nutrition 2009 Okinawa Sweet Potato is highly anti-inflammatory !
http://www.nutritiondata.com/facts/vegetables‐and‐vegetable‐products/2667/2 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 suggesting that isoflavones might prove useful for the prevention and/or treatment of prostate cancer (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 pigmentis 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
Activation of FOXO3a by the Green Tea Polyphenol Epigallocatechin-3-Gallate ( ECGC) Induces Estrogen Receptor α Expression Reversing Invasive Phenotype of Breast Cancer Cells
Belguise K et al. Cancer Res 2007;67:5763-5770
©2007 by American Association for Cancer Research Okinawa Traditional Dietary Intervention Study in Americans Vacuum Packed Bento Okinawa Diet Intervention Achieves “DASH*-like” Blood Pressure Reductions in Americans
130
A group intervention 120
1. SBP reduced 2.6 mm Hg (95% CI -4.3, -1.2. 110 2. DBP reduced 2.1mm Hg (95%CI -3.1 -1.0) B group intervention and 0.3mmHg (95%CI -2.1 0.6). SBP(A group) 3. 24h-urinary sodium and body weight SBP(B group) 100 reduced (between-group differences DBP(A group) ranged from p=0.032 to 0.0002). DBP(B group)
odpesr( m Hpressure(m g) B lood 90
*Dietary Approaches to Stop 80 Hypertension (DASH:
Most common physician prescribed 70 diet to lower high blood pressure in the U.S. 023 Month
Todoriki et al J Hypertension 2008 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 102102 YearsYears YoungYoung andand StillStill DigginDiggin’’ LifeLife
DomoDomo Arigato!Arigato! Mahalo !
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)