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Promoting Healthy Aging Through Nutrigenomics: the Potential of the Traditional Okinawan Diet

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Promoting Healthy Aging Through Nutrigenomics: the Potential of the Traditional Okinawan Diet 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 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 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
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