Caloric restriction (CR) - or reduced calorie intake with nutritional maintenance - can extend lifespan and increase resistance to age-related disease by mechanisms which likely involve reduced oxyradical production and cellular hormesis responses in which genes encoding cytoprotective proteins are upregulated. Recent studies suggest that several of the anti-aging effects of CR can be mimicked by giving animals compounds that reduce energy availability at the cellular level. Such CR mimetic compounds (e.g., 2-deoxy-D-glucose, phenformin and iodoacetate) have proven beneficial in experimental models of neurodegenerative disorders and cancer. CR mimetics appear to act via a hormesis-based mechanism in which cells upregulate heat-shock and other chaperone proteins, and growth factors. Although long-term effects of dietary supplementation with such CR mimetics remain to be determined, the initial findings reviewed here suggest a novel approach for the investigation of basic mechanisms of aging, for the possible extension of lifespan without CR, and for dealing with the rising tide of obesity in industrialized countries.
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