The genetics of aging.

The genetic analysis of life span has only begun in mammals, invertebrates, such as Caenorhabditis elegans and Drosophila, and yeast. Even at this primitive stage of the genetic analysis of aging, the physiological observations that rate of metabolism is intimately tied to life span is supported. In many examples from mice to worms to flies to yeast, genetic variants that affect life span also modify metabolism. Insulin signaling regulates life span coordinately with reproduction, metabolism, and free radical protective gene regulation in C. elegans. This may be related to the findings that caloric restriction also regulates mammalian aging, perhaps via the modulation of insulin-like signaling pathways. The nervous system has been implicated as a key tissue where insulin-like signaling and free radical protective pathways regulate life span in C. elegans and Drosophila. Genes that determine the life span could act in neuroendocrine cells in diverse animals. The involvement of insulin-like hormones suggests that the plasticity in life spans evident in animal phylogeny may be due to variation in the timing of release of hormones that control vitality and mortality as well as variation in the response to those hormones. Pedigree analysis of human aging may reveal variations in the orthologs of the insulin pathway genes and coupled pathways that regulate invertebrate aging. Thus, genetic approaches may identify a set of circuits that was established in ancestral metazoans to regulate their longevity.