IGF-1 and insulin signaling in the control of longevity

In the laboratory mouse, there are three spontaneous mutations and one gene knockout that induce primary deficits in endocrine signaling and prolong life. Increased life expectancy appears to be due to delayed aging in at least three of these four mutants. Ames dwarf (Prop(df)) and Snell dwarf (Pit1(dw)) mice have primary deficiency of growth hormone (GH), prolactin and thyrotropin, little (GHRHR(lit)) mice have GH releasing hormone resistance, and GHR-KO mice are GH resistant. Reduced GH secretion or action leads, in each case, to the expected precipitous decline in peripheral levels of insulin-like growth factor-1 (IGF-1), the key mediator of GH actions. The role of reduced IGF-1 signaling in mediating the effects of these four "longevity genes" in the mouse is consistent with the findings in Caenorhabditis elegans and Drosophila melanogaster. However, the formal proof of a cause-effect relationship between reduced IGF-1 levels and delayed aging remains to be obtained, and the mechanisms of IGF-1 action on aging remain to be identified. As expected from the anti-insulin actions of GH and from its effects on the pancreatic islets, insulin regulation of peripheral glucose levels is significantly altered in dwarf and GHR-KO mice. These alterations include reductions in basal and glucose-stimulated insulin levels, enhanced sensitivity of the liver to insulin, and reduced plasma glucose levels. Surprisingly, indices of enhanced sensitivity to insulin coexist with reduced ability to dispose of a glucose load. As in the case of IGF-1 signaling, a role of reduced insulin signaling in extending longevity is strongly supported by data from invertebrates. In Ames dwarf mice, there is evidence for increased activity of antioxidant enzymes and reduced oxidative damage of mitochondrial DNA and other cell components. Data derived from animals subjected to caloric restriction (CR) suggest that there is considerable overlap of phenotypic characteristics of long-lived dwarf and GHR-KO mice with those of normal (wild type) animals subjected to CR. These include reductions in plasma insulin and glucose levels, core body temperature, growth, adult body size, and fertility. However, there are also considerable differences, including discordant changes in body composition and in spontaneous locomotor activity and differences in the profiles of hepatic gene expression. Ongoing studies of the interactions of CR and longevity genes suggest additive effects on longevity in at least one of these mutants, the Ames dwarf. Effects of CR on plasma insulin and glucose levels in GHR-KO mice resemble its actions in wild type animals, while CR effects on corticosterone levels are distinctly different. In summary, results available to date suggest that reduced function of the somatotropic axis and reduced IGF-1 and insulin signaling mediate the action of several mutations on aging and life span of laboratory mice. The mechanisms linking these neuroendocrine changes to delayed aging remain to be identified, but it is reasonable to suspect that reduced generation of reactive oxygen species and reduced oxidative damage to DNA and other macromolecules are involved and ultimately responsible for prolonged longevity.