The GH/IGF-I axis and longevity

Inserm U515, Hopital Saint-Antoine, 184 rue Fbg St-Antoine, 75571 Paris 12, France. holzenberger@st-antoine.inserm.fr

Several converging lines of evidence obtained over the last years in a wide variety of experimental model organisms suggest that the ageing process is regulated by genes that encode proteins from the somatotroph axis: longevity genes like daf-2, which were identified using mutant Caenorhabditis elegans strains, turned out to be orthologues of the mammalian genes encoding insulin-like signalling cascade proteins. Transgenic flies with mutations in the corresponding insect genes showed a similar pattern of increased lifespan. Finally, mice with spontaneous mutations leading to pituitary hormone deficiency significantly outlived controls. While these and other genetic models suggest that the downregulation of the somatotroph axis can slow the ageing process, other results from studies using pharmacological administration of growth hormone suggest that such stimulating treatment can restore some of the phenotypic traits associated with youth. To better understand the role of the insulin-like receptors in mammalian lifespan regulation and ageing, we explored the phenotype of heterozygous IGF-I receptor (IGF1R) knockout mice. Compared with control littermates these mutants live longer without any obvious impairment of their health and physiology, except a reduced glucose tolerance that we observed in males. These IGF1R(+/-) mutants were also more resistant to oxidative stress in vivo, and we identified a possible molecular pathway linking underphosphorylation of IGF-I receptors to the lack of activation of p66Shc, a protein capable of increasing resistance to oxidative stress through regulation of a set of downstream genes. These and other results suggest that in mammals too, lifespan can be increased by continuous, long-term downregulation of IGF signalling. Since growth hormone administration normally stimulates IGF production in tissues, the question arises whether the beneficial effects of GH, as reported by others, could be IGF independent. This hypothesis can be addressed, for example, by adequately combining existing transgenic mouse models.

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