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Endocrine regulation of ageing

Nature Reviews Molecular Cell Biology volume 8, pages 681–691 (2007)Cite this article

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.

Abstract

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.

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Figure 1: Cell non-autonomous regulation of lifespan by insulin/insulin-like growth factor-1 signalling in worms.
Figure 2: Cell non-autonomous regulation of lifespan by insulin/IGF1 signalling in flies.
Figure 3: Regulation of lifespan by insulin/IGF1 signalling in mice.
Figure 4: Regulation of lifespan by lipophilic signals in worms and flies.
Figure 5: Possible regulation of lifespan by steroid hormones in mice.

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Authors and Affiliations

  1. Joslin Diabetes Center and Harvard Medical School, 1 Joslin Place, Boston, 02215, Massachusetts, USA

    Steven J. Russell & C. Ronald Kahn

  2. Steven J. Russell & C. Ronald Kahn

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Glossary

Dauer

A long-lived alternative larval stage in worms that is stress and starvation resistant.

Fat body

A fat storage depot in flies that is divided into the cerebral and peripheral fat bodies. FOXO activation in the fat body is sufficient to prolong lifespan.

Diabetic ketoacidosis

Metabolic derangement in the absence of adequate insulin signalling, characterized by marked hyperglycaemia and the excess production of organic acids that are derived from lipolysis.

Insulin resistance

A state characterized by a requirement for elevated levels of insulin to maintain normoglycaemia. Insulin resistance is the earliest defect in the progressive pathogenesis of type-2 diabetes mellitus and is present in individuals who are obese or who have the metabolic syndrome.

Leptin

A peptide hormone produced by adipocytes that negatively regulates food intake and positively regulates metabolic rate. Both leptin deficiency and leptin resistance are associated with obesity. Leptin levels are low in mammals on caloric restriction.

Adiponectin

A peptide hormone that is produced by adipocytes in an amount that is inversely proportional to fat mass. Increased adiponectin levels are associated with increased insulin sensitivity.

Protein deacetylase

An enzyme that removes acetyl groups from N-acetyl-lysine residues in proteins. Some of the sirtuins, including SIRT1, have deacetylase activity.

Resveratrol

A plant terpenoid compound that can activate the deacetylase activity of SIRT1 and orthologous sirtuins.

Glycosidase family-1 enzyme

One of a related family of enzymes that hydrolyze glycosidic bonds between monosaccharide components of polysaccharides.

Steroid glucuronide

A steroid modified by the covalent addition of glucuronic acid via a glycosidic bond, with the usual effect of increasing water solubility and decreasing biological activity.

Corpora allata

A neuroendocrine organ that is attached to the brain of flies and produces juvenile hormone and ecdysone in response to insulin/IGF1-like signalling.

Diapause

A state of decreased metabolic activity during which reproduction is suspended to await improved conditions.

Pregnane

A steroid with 21 carbons. Examples include pregnenolone or progesterone.

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Russell, S., Kahn, C. Endocrine regulation of ageing. Nat Rev Mol Cell Biol 8, 681–691 (2007). https://doi.org/10.1038/nrm2234

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