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19 Mammalian Metabolism in Aging

Pere Puigserver, C. Ronald Kahn


Life span in organisms is controlled by a complex interaction of genetic and metabolic factors. Although in lower organisms, some of these factors that determine longevity have been identified, in mammals, they are largely unknown. In this chapter, we focus on the metabolic factors associated with aging. Perhaps the most striking evidence that the aging process is under strict metabolic control comes from the highly investigated effects of caloric restriction in extending life span. There are several theories of aging which support the concept that metabolic stability is a major factor that determines life span. We concentrate on the main metabolic/signaling pathways that favor anabolic or catabolic responses and are altered as mammals age.

It is well established that food restriction reduces age-dependent mortality and prolongs life span of animal species ranging in complexity from single-cell organisms to mammals (Masoro 2005). Insulin signaling was first linked to life span when it was shown that mutations in daf-2 dramatically lengthen the life span of Caenorhabditis elegans (Kenyon et al. 1993), and daf-2 was found to encode the C. elegans homolog of the insulin and insulin-like growth factor-1 (IGF-1) receptors (Kimura et al. 1997). During the past 15 years, an extensive body of work has shown that mutations in many genes in pathways homologous to the insulin and IGF-1 signaling pathways of mammals can prolong the life span of the nematode worm C. elegans and the fruit fly Drosophila melanogaster (for review, see Tatar et al. 2003; Kenyon...

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