Calorie Restriction Retards the Aging Process by Inducing Sirtuins and Uncoupling Protein 3, Thereby Reducing the Production of Reactive Oxygen Species.

Calorie restriction is the only experimental manipulation that prolongs longevity in experimental animals. The life prolonging effects of calorie restriction are related to a lower incidence of tumors and less inflammation, but more importantly, a lower generation of reactive oxygen species (ROS). This effect is related to the overexpression of two groups of enzymes. One is a group of (NAD+)-dependent deacetylases called sirtuins whose main actions are to increase free fatty acid flow from adipose tissue, improve insulin secretion and promote mitochondrial biogenesis in muscle. The other group corresponds to uncoupling proteins (UCP), specially UCP 3 that reduces the mitochondrial production of ROS. On the other hand, an effect of calorie restriction that is always reported, is a decrease in resting energy expenditure. A reduction in the activity of UCP1 in brown adipose tissue could be a mechanisms to explain this effect. However sirtuins apparently increase the expression of UCP1.Recently PET CT scans have emerged as a non invasive methodology to recognize brown adipose tissue activity and indirectly, UCP1 activity. Also measurement of telomere length in peripheral blood mononuclear cells has consolidated as a good marker of aging. Two possible models of calorie restriction can be studied in humans. One is a retrospective model in which adults are separated in those that have maintained a stable weight during adulthood in a manner analogous to the weight clamp model of calorie restriction in non human primates. This model is only reliable if there are objective records of the weight that the studied subjects had 20 or more years ago. In the retrospective part of this project the investigators propose to study adults whose weight was recorded previously. The investigators pretend to compare telomere length and expression of SIRT1 and 6 in PBMC, plasma 8 isoprostanes and carotid intima media thickness between weight maintainers and weight gainers. The investigators hypothesis is that weight maintainers will have a better aging profile than weight gainers. In the prospective part of the project the investigators will study a human model of calorie restriction prescribing a 25% reduction in calorie intake during 3 months and comparing groups according to weight loss. At baseline and the end of the study period, UCP3 and SIRT1 expression in muscle biopsies, SIRT1 and 6 expression in PBMC and brown adipose activity, assessed by 18fluorodeoxyglucose uptake using PET/CT will measured. The investigators hypothesis is that individuals subjected to calorie restriction will experience an increase in the expression of UCP3, SIRT1 and SIRT6 and a reduction in brown adipose tissue activity. Simultaneously, these subjects will experience a reduction in oxidative stress markers in muscle and plasma.