Longevity and Calorie Restriction Calorie restriction is healthy and prolongs life. A 50% calorie restriction doubles the life- span of C. e legans wo

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1 Anti-Aging Interventions Frank Greenway, MD Kinexum-Pennington Conference July 18, 2013

2 Longevity and Calorie Restriction Calorie restriction is healthy and prolongs life. A 50% calorie restriction doubles the life- span of C. e legans worms, flies, yeast and mice. 25% calorie restriction in humans reduces weight 10% in 6 months, reduces metabolic rate and insulin levels and insulin resistance. It was once thought that a reduction in metabolic rate was needed to prolong life. Good RA et al. Am J Path, 1976

3 Calorie Reduction Increases Longevity (Reduced Food Intake in Worms) F IG. 1. Four alleles of eat- 2 lengthen life span. The percentage of worms alive on a given day after eggs being laid for a single experiment: N2 (D), eat- 2(ad465) (E), eat- 2(ad453) ( ), eat-2(ad1113) ( ), and eat- 2(ad1116) (F). Larsen PL et al. Genetics. 1995;139(4):

4 Longevity and M ethionine Restriction M ethionine restriction is healthy and prolongs life. M ethionine restriction increases food intake, and metabolic rate, but decreases insulin, insulin resistance and body weight. Longevity may be associated with a reduction in insulin and an increase in insulin sensitivity Orentreich et al. J Nutr, 1993

5 M ethionine 120 Restriction Extends Rats Life in 100 Survival Percent % Met 0.17% Met 20 0 Orentreich et al. J Nutr, 1993

6 M ethionine Metabolic Restriction Increases Rate More When Awake Day Night Control Methionine Restricted Malloy VL et al. Aging Cell. 2006;5(4):305-14

7 Change in Body Weight in Grams Body Weight Orentreich et al. J Nutr, % Met 0.17% Met

8 Change in Percent Body Fat Body Fat Percent Control Methionine Restricted 5 0 Orentreich et al. J Nutr, 1993

9 Change in Food Intake gm body Weight Food Intake per Orentreich et al. J Nutr, % Met 0.17% Met

10 Methionine, Cancer and Humans M ethionine cells. restriction is harmful to cancer Normal cells can re-methylate homocysteine for the m ethionine they need but cancer cells are deficient in this function A safety study to evaluate restriction in humans was patients without cachexia methionine done in cancer over 17 weeks

11 Safety M ethionine restricted m ethionine per day in 8 cancer patients T he cancer patients weight/week M ethionine fell 58% lost 0.5% of to 2mg/kg their body Albumin and pre-albumin did not decrease Calorie intake increased and methionine r estriction was s afe f or 17 weeks. E pner DE et al. Nutr and Cancer. 42(2):158-66, 2002

12 Weight Loss of 0.5% of Body Weight per Week E pner DE et al. Nutr and Cancer. 42(2):158-66, 2002

13 M ethionine Intake was Reduced Dramatically E pner DE et al. Nutr and Cancer. 42(2):158-66, 2002

14 Food Intake Increased E pner DE et al. Nutr and Cancer. 42(2):158-66, 2002

15 Change in 24 hour Methionine Fat Oxidation 16 wk Restriction PBRC Fat Oxidation, p< Fat Oxidation 0-10 Methionine replete Methionine deficient Plaisance EP et al. J Clin Endocrinol Metab. 2011;96(5):E836-40

16 Longevity and Reproduction Diet restriction extends life and reduces fecundity decreasing normal egg production Longevity and decreased fecundity reversed by essential amino acids. are M ethionine alone can restore fecundity without reversing longevity. With proper balance of nutrients one can have both fecundity and healthy longevity Grandison RC et al. Nature. 462: , 2009

17 Aging and Caloric Restriction Caloric restriction extends lifespan for yeast, C. elegans worms, drosophila flies and rodents In C. elegans worms, the Daf- 2 gene is the homolog of the insulin receptor. When this gene is knocked out, longevity is increased. Suggesting that reductions in insulin signaling is involved in aging. M annoheptulose from a vacados is an inhibitor of g lucokinase and inhibits insulin secretion.

18 Less Insulin Signaling Increases Lifespan

19 M annoheptulose 15mmol/L Insulin Secretion Reduces Zhou Y et al. Metabolism. 1999;48(7):

20 The Glucokinase Pathway

21 Studying Anti- Aging Compounds Humans Insulin sensitivity is a potential marker for longevity in humans. For example: testing insulin sensitivity in humans treated with a vacadoes or mannoheptulose Treating elderly people randomized to a food intervention vs. a placebo measuring death, since anti- aging interventions in lower animals work at any age. in

22 Conclusions The common theme of anti- aging agents seems to be insulin sensitivity, not food intake or metabolic rate. A vacadoes contain m annoheptulose which decreases insulin secretion suggesting a reduction in insulin resistance. A vacadoes await a clinical trial measuring insulin sensitivity or longevity.

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