Endocrine regulation of ageing

Mutations in single genes can increase the lifespans of lower metazoan organisms (worms and flies) and mammals. Many of these mutations affect genes that are involved in endocrine signalling pathways.Attenuation of signalling through the insulin/insulin-like growth factor-1 (IGF1) pathways prolongs the lifespans of worms and flies. Decreased IGF1 signalling also prolongs lifespan in mammals; however, diminished insulin signalling has been shown to prolong lifespan in mammals only when limited to adipocytes.The regulation of ageing by some hormone-receptor pathways is cell non-autonomous; genetic changes in a small group of cells can alter the lifespan of the whole organism. For example, worms that carry mutations in the insulin/IGF1 pathway in only a few cells are long-lived, and mice with a fat-specific insulin-receptor deficiency are also long-lived.Lipophilic hormones, including steroids, also modulate ageing in worms and flies. Related lipophilic hormones are present in mammals; however, the role of lipophilic hormones in regulating mammalian ageing has not yet been defined.A protein encoded by the Klotho gene can circulate in the blood and might function as a hormone. Overexpression of Klotho prolongs lifespan, possibly by altering insulin signalling.The regulation of lifespan by cell non-autonomous endocrine pathways might allow exploitation of the inherent specificity of hormone–receptor interactions to alter the ageing process.