Strategies For A Healthy, Longer Life: A Review Of The Current Literature

1. Strategies For A Healthy, Longer Life: A Review Of The Current Literature Joe D. Goldstrich, MD, FACC, CNS

2. Learning Objectives Participants will: Become aware of nutritional measures associated with longevity. Become aware of nutritional supplements associated with a longer life and improved cognition. Become aware of current research on hormone therapies (including growth hormone) for longevity and improved cognition.

3. Hope Drives Antiaging Hype Antiaging, longevity, and age-management clinics and institutes offer benefits that would appear to the appropriately skeptical eye to be too good to be true. Some advertisers claim that with their products or services you can do some or all of the following: � Reverse 2 decades of aging � Live to be 125 or older � Give yourself a natural face-lift and body muscle rejuvenation � Substantially reduce your adipose tissue � Increase your skin thickness and elasticity � Increase your lean body mass � Increase your physical strength and energy Editorial: CLEVELAND CLINIC JOURNAL OF MEDICINE, DECEMBER 2006

4. Dietary Strategies Eat what the centenarians eat Restrict calories while maintaining good nutrition Don�t get too skinny or too fat

5. Eat What The Centenarians Eat The Blue Zones by Dan Buettner They all have an active lifestyle Sardinia Red wine Goat�s milk and cheese Plant based diet with small amounts of red meat Loma Linda, CA- Seven Day Adventists Nuts �Vegetarian� with an early, light dinner Drink plenty of water

6. Specific nuts with research that supports cardiovascular health Almonds Walnuts Peanuts (legume) skins Macadamia Pistachio most phytosterols Chestnuts Pecans +/- Hazelnuts

7. Okinawa, Japan hara hachi bu : stop eating when 80% full Plant based diet with soy Costa Rica Hard water: calcium in the water Largest meal in the morning Lightly salted corn tortillas, beans and squash Not much meat, some eggs

8. Ikaria, Greece: currently being researched The Ikarian variation of the Mediterranean Diet is high in vegetables & beans, and low in meat & sugar; not much fish, but high in potatoes Wild Greens Herbal Teas Goat's milk

9. Anatomy of health effects of Mediterranean diet: Greek EPIC prospective cohort study CONCLUSION: The dominant components of the Mediterranean diet score as a predictor of lower mortality are moderate consumption of ethanol, low consumption of meat and meat products, and high consumption of vegetables, fruits and nuts, olive oil, and legumes. Minimal contributions were found for cereals and dairy products and for fish and seafood, the intake of which is low in this population. BMJ. 2009 Jun 23;338

10. Caloric Restriction and Longevity Calorie-Counting Monkeys Live Longer Science News 9 July 2009 Canto, left, a 27-year-old rhesus monkey, is on a restricted diet, while Owen, 29, is not.

11. Caloric Restriction and Longevity Previous caloric restriction studies successful in mice, rats, worms and yeast 30% fewer calories than usual vs. free-feeding Vitamin and mineral supplements to prevent malnutrition Diet was stared in monkeys as they reached young adulthood (7-14 years old) Average normal lifespan 27 years; max 40 Leaner diets reduced deterioration of muscle and brain gray matter, two conditions associated with aging. 63% of the calorie-restricted animals are still alive compared to only 45% of their free-feeding counterparts Science. 2009 Jul 10;325(5937):201-4

12. BMI and Mortality  Reduction in relative risk of developing major chronic diseases such as cardiovascular disease, diabetes, and cancer associated with 4 healthy lifestyle factors among German adults never smoking, having a body mass index (BMI) lower than 30 (most predictive) performing at least 3.5 hours per week of physical activity following a healthy diet Arch Intern Med.,�2009 Aug 10/24 Overall, people who were overweight but not obese � defined as a body mass index of 25 to 29.9 � were actually less likely to die than people of normal weight, defined as a B.M.I. of 18.5 to 24.9. People who were underweight, with a B.M.I. under 18.5, were more likely to die than those of average weight. A little excess weight seems to be protective for the elderly, who are at greatest risk for dying. Obesity, 2009 Jun 18

13. Supplements

14. Resveratrol BACKGROUND: Sirtuin 1-7 (SIRT1-7) are deacetylases that are dependent on NAD(+) for their activity. SIRT1 down-regulates p53 activity, increasing lifespan, cell survival, and neuroprotection; it also deacetylates peroxisome proliferator-activated receptor-gamma and its coactivator 1alpha, promoting fat mobilization, increasing mitochondrial size and number, and positively regulating insulin secretion. Sirtuins link nutrient availability and energy metabolism. Calorie restriction, which increases lifespan and is beneficial in age-related disorders, activates sirtuin. Major efforts are thus focused to developing sirtuin activators. Expert Opin Ther Pat. 2009 Apr;19(4):403-14

15. To date, resveratrol is the most potent natural compound able to activate SIRT1, mimicking the positive effect of calorie restriction. Resveratrol might help in the treatment or prevention of obesity and in preventing the aging-related decline in heart function and neuronal loss. Resveratrol is found in grape skins (red wine > white), red peanut skins, some berries & the root of Polygonum cuspidatum (Japanese Knotweed)

16. Potential Benefits of Resveratrol Inhibits the proliferation of a variety of human cancer cell lines, including those from breast, prostate, stomach, colon, pancreatic, and thyroid cancers. It is not known whether high intakes of resveratrol can prevent cancer in humans. Increases the lifespan of yeast, worms, fruit flies, fish, and mice fed a high-calorie diet, but it is not known whether resveratrol will have similar effects in humans.

17. May be the ingredient in red wine responsible for many cardiovascular benefits: antioxidant, angiogenic, antihypercholesterolemic, antidiabetic, and cardioprotection during myocardial infarction. Can J Physiol Pharmacol. 2009 Apr;87(4):275-86 Resveratrol, via its antioxidant and anti-inflammatory properties, has the potential to inhibit the progression of atherosclerosis by blocking IL-18 Am J Physiol Heart Circ Physiol. June 26, 2009

18. Potential Downside of Resveratrol To replicate the dosages of the mice studies in humans requires about 400 mg of resveratrol daily for a 175 pound individual. (a 5 oz glass of red wine has from 0.3 to less than 2 mg resveratrol) May help protect the liver in rats on a high fat diet but increasing oxidative stress on a normal diet. Food Chem Toxicol. 2009 Jun There is increasing evidence that resveratrol exhibits pro-oxidant activity under certain experimental conditions, causing oxidative DNA damage that may lead to cell cycle arrest or apoptosis. Arch Biochem Biophys. 2009 Jun 15;486(2):95-102

20. Nutritional Supplements: Vitamin D Prevalence of vitamin D insufficiency in patients with Parkinson Disease and Alzheimer Disease. Arch Neurol. 2008 Oct;65(10):1348-52 Childhood asthma may be a consequence of vitamin D deficiency. Curr Opin Allergy Clin Immunol. 2009 Jun;9(3):202-7 The vitamin D receptor agonist elocalcitol inhibits IL-8-dependent benign prostatic hyperplasia stromal cell proliferation and inflammatory response by targeting the RhoA/Rho kinase and NF-kappaB pathways. Prostate. 2009 Apr 1;69(5):480-93 Vitamin D and breast cancer. Ann Epidemiol. 2009 Jul;19(7):462-7 Vitamin D for cancer prevention: global perspective. IBID 468-83 Dietary vitamin D and cancers of the oral cavity and esophagus. Ann Oncol. 2009 Jun 1 Vitamin D deficiency and chronic lung disease. Can Respir J. 2009 May-Jun;16(3):75-80

21. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2009 Feb 23;169(4):384-90 Association between 25-hydroxyvitamin D levels and cognitive performance in middle-aged and older European men. J Neurol Neurosurg Psychiatry. 2009 Jul;80(7):722-9 Vitamin D, a neuro-immunomodulator: Implications for neurodegenerative and autoimmune diseases. Psychoneuroendocrinology. 2009 Jun 20 Does vitamin D reduce the risk of dementia? J Alzheimers Dis. 2009 May;17(1):151-9 For a complete list of Vitamin D Research, see the Vitamin D Council at: http://www.vitamindcouncil.org/

22. Vitamin D and Alzheimer's 1alpha,25-dihydroxyvitamin D Interacts with Curcuminoids to Stimulate Amyloid-beta Clearance by Macrophages of Alzheimer's Disease Patients. J Alzheimers Dis. 2009 May 11 There are 2 types of macrophages in Alzheimer�s patents. Macrophages typically clear plaques in healthy patients, but don't do so in Alzheimer's patients. The researchers found that vitamin D had strong immunostimulating effects on amyloid-beta phagocytosis in both of the types of macrophages in Alzheimer's patients. Curcuminoids in combination with vitamin D significantly increased total amyloid-beta uptake compared with D alone, but only in Type I macrophages. Curcuminoids enhance the surface binding of amyloid beta to macrophages, while vitamin D strongly stimulated the uptake and absorption of amyloid beta, resulting in a benefit through both genomic and nongenomic effects.

23. Vitamin D and Heart Dicease Vitamin D deficiency is associated with increased occurrence of coronary heart disease, hypertension, insulin resistance, congestive heart failure and cardiovascular mortality.

24. Vitamin D sufficiency is associated with: Downregulation of the RAAS and lower BP Improved glycemic control Improved cardiac muscle function Decreased coronary calcification Decreased risk for cardiovascular events and mortality J Am Soc Nephrol. 2009 May 14 J Am Coll Cardiol. 2008 Dec 9;52(24):1949-56 Am J Med Sci. 2009 Jul;338(1):40-4 Pharmacotherapy. 2009 Jun;29(6):691-708

25. How much Vitamin D? Vieth reviewed the extensive literature supporting the low likelihood of toxicity of vitamin D3 at intakes of 2000�4000 IU/day and reported that toxicity may be unlikely even at doses as high as 10,000 IU/day (7). His review suggests that a serum 25(OH)D target of 60 ng/ mL (150 nmol/L) may be optimal for most individuals. Annals of Epidemiology 19: (7) 441-445 (July 2009)

26. Other Supplements With Anti-aging Potential Multivitamin use and telomere length in women. Am J Clin Nutr 2009;89:1857�63. Vitamin C & E also corrolated with telemore length Deceleration of Senescence in Normal Human Fibroblasts by Withanone Extracted From Ashwagandha Leaves. J Gerontol A Biol Sci Med Sci. 2009 Jul 8 Ashwagandha is an Ayurvedic shrub. It increased the in vitro division potential of normal human cells that appeared to be mediated by decreased accumulation of molecular damage, downregulation of the senescence-specific beta-galactosidase activity and the senescence marker protein, p21(WAF-1), protection against oxidative damage, and induction of proteasomal activity Dietary antioxidants, such as curcumin, L-carnitine/acetyl-L-carnitine and carnosine have recently been demonstrated in vitro to be neuroprotective. Front Biosci. 2009 Jan 1;14:376-97 Quercetin effects on VO2max and exercise capacity Int J Sport Nutr Exercise Metab 2009

27. Anything new on Vitamin E? Gamma-tocopherol (GT) supplementation alone and in combination with alpha-tocopherol (AT) alters biomarkers of oxidative stress and inflammation in subjects with metabolic syndrome (MetS) In MetS subjects, the combination of AT + GT therapy results in significant increases in AT and GT concentrations as well as their metabolites in plasma and urine, as well as significant reductions in hsCRP, urinary nitrotyrosine, and lipid peroxides. These results point to the superiority of combined AT + GT supplementation in ameliorating both oxidative and nitrative stress and inflammation in MetS subjects Free Radic Biol Med. 2008 March 15; 44(6): 1203�1208

28. Hormones for Longevity and Cognition Estrogen: Overall, the evidence does not convincingly support the prescription of early or late postmenopausal estrogen therapy to preserve cognitive function or prevent dementia. (breast cancer) Semin Reprod Med. 2009 May;27(3):275-82 Testosterone: Although bioavailable testosterone is inversely correlated with cognitive decline and higher levels of testosterone are associated with better mental control and long-term verbal memory, studies of testosterone therapy to enhance cognition have shown mixed results. (cholesterol, hematocrit, +/- prostate cancer) CLEVELAND CLINIC JOURNAL OF MEDICINE, DECEMBER 2006

29. Dehydroepiandrosterone (DHEA): Cognitive dysfunction has been associated with low, normal, and high DHEA(S) levels. One review discussed improvement of learning and memory dysfunction after DHEA supplementation in people with low DHEAS levels, but another study failed to detect any significant cognitive effects after DHEA administration. CLEVELAND CLINIC JOURNAL OF MEDICINE, DECEMBER 2006

30. Growth Hormone (GH) Statement by the Growth Hormone Research Society on the GH/IGF-I Axis in Extending Health Span: "Until future clinical research in this area is conducted, in particular carefully designed, long-term studies, using validated outcome parameters, the clinical use of GH or GHS in older adults, alone or in combination with testosterone, cannot be recommended.� (carpal tunnel syndrome, lower-extremity edema, diffuse arthralgia, and diabetes in more than one third GH treated individuals) J Gerontol A Biol Sci Med Sci. 2009 Jul 8 Editorial by Editor of Archives of Gerontology & Geriatrics: "There is no doubt that the Adult Growth Hormone Deficiency Syndrome (AGHDS) shows a close similarity with most of the age-dependent functional losses. It has also been shown that replacement therapy is beneficial in all aspects of the AGHD pathology, therefore, we have all the reasons to consider aging as an AGHD syndrome." Arch Gerontol Geriatr. 2009 May-Jun;48(3):271-5

31. Still Gonna Die