Effect of calorie restriction in extending life span is discussed with particular reference to possible molecular mechanisms underlying this effect. Aspects considered include: increases in life span of organisms (yeasts, nematodes, insects and mammals) resulting from calorie restriction; the 'passive' theory of aging, involving reactive oxygen species produced during respiration causing oxidative damage to DNA, RNA, protein and lipids; the classical mechanistic explanation of the effect of calorie restriction on aging, involving a decrease in the load of reactive oxygen species that results in less damage and thus an increased life span; the 'active' theory of aging that depends on a genetic determinant of life span; Sir2 (silent information regulator), the gene determining the increase in life span resulting from calorie restriction in yeasts, nematodes and Drosophila; discovery of the Sirt1 gene in mammals, an ortholog of Sir2, which controls the metabolism of white adipose tissue; the possibility that Sirt1 could be the mechanism whereby calorie restriction lengthens life span in mammals; role of the Sirt1 gene in mammals in controlling expression of a multitude of metabolic and neuroendocrine systems; activation of Sirt1 by calorie restriction in mammals and expression of Sirt1 protein; and inhibition by Sirt1 protein of peroxysome proliferator-activator receptor gamma (PPARgamma), the nuclear receptor that promotes adipogenesis. It is concluded that lowering of adiposity seems to be one mechanism, but not the only way, by which calorie restriction affects life span in mammals.
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