Caloric restriction: life span extension and retardation of brain aging

Caloric restriction (CR) increases maximum life span in many species. In laboratory rodents, it opposes the development of age-associated biological and pathological changes. Although most rodent studies start CR early in life (similar to1-3 months of age), CR from middle age also retards the aging process. Reviewed herein is the approach we are taking to address three questions concerning CR. How does CR retard aging and disease processes? There is evidence that CR lowers oxidative stress generated by mitochondrial oxidative energy (i.e. calorie) metabolism. This lowering is most profound in post-mitotic tissues. We have used microarrays to describe the gene expression profile of aging skeletal muscle, heart and brain (neocortex and cerebellum) in mice and its alteration by CR. In both brain regions, aging resulted in an expression profile indicative of a marked inflammatory response, oxidative stress, and reduced neurotrophic support. CR attenuated the age-associated inductions of genes involved in inflammatory and stress responses while shifting expression levels for several genes not changing with age. Does CR retard aging in primates? Two ongoing studies in rhesus monkeys on CR plus epidemiological data support the idea of human translatability. Whether life extension occurs in monkeys on CR should become known in similar to15 years. Studies in humans on CR were launched by the NIA in 2002. Can substances be found which mimic the beneficial actions of CR? The search for 'CR mimetics' should benefit from the use of genomic and proteomic approaches. (C) 2003 Elsevier Science B.V. All rights reserved.