Endocrine regulation of ageing

Key Points 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. Mutations in genes that regulate endocrine signalling pathways can increase the lifespans of worms, flies and mammals. Endocrine pathways might therefore serve as targets for the manipulation of the ageing process and prevention of age-related diseases. Over the past 15 years it has become clear that mutations in genes that regulate endocrine signalling pathways can prolong lifespan. Lifespan can be increased by altered endocrine signalling in a group of cells or a single tissue, which indicates that crosstalk between tissues functions to coordinate ageing of the organism. These endocrine pathways might serve as targets for the manipulation of the ageing process and prevention of age-related diseases.