The role of insulin-like signalling in the regulation of ageing.
Inactivation of insulin-like growth factor I (IGF-I) signalling pathways have been shown to extend lifespans in various lower species, including the nematode Caenorhabditis elegans. In order to investigate this relationship in a mammalian species, a series of experiments were carried out with a mouse model heterozygous for a mutation in the IGF-I receptor gene. These heterozygous mice only had slight post-natal growth retardation, but had a lifespan 26% longer than normal. Their fertility and dietary intake were unaffected. The mechanism for increased lifespan in these mutant mice appears to be enhanced resistance to oxidative stress: heterozygous mice had a greater survival rate subsequent to severe oxidative stress generated in vivo than wild-type mice, and cells from heterozygous animals had a better resistance to hydrogen peroxide in vitro than cells from wild-type animals. Resistance to oxidative stress in these mutant animals could be caused by decreased phosphorylation of molecules downstream of the IGF-I receptor in the IGF-I signalling pathway, one of which is thought to be p66shc. Whether this link between reduced IGF-I signalling and longevity is conserved in other mammalian species, including humans, is presently not known. If it was, it could have implications for growth hormone therapy, which increases serum IGF-I levels.
Holzenberger
M
M
INSERM, Hôpital Saint-Antoine, Paris, France. Martin.Holzenberger@st-antoine.inserm.fr
D000375:Aging / Q000502:physiology*; D000818:Animals; D015536:Down-Regulation; D005260:Female; D006579:Heterozygote; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008136:Longevity / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D010269:Paraquat / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000235:genetics; D015398:Signal Transduction
D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D010269:Paraquat