Institut National de la Sante et de la Recherche Medicale U515, Hopital Saint-Antoine, 75571 Paris 12, France
Service d'Anatomie et de Cytologie Pathologiques, Hopital Saint-Antoine, 75571 Paris 12, France
Institut National de la Recherche Agronomique, 37380 Nouzilly, France
Institut National de la SantŽ et de la Recherche Medicale U352, INSA, 69621 Villeurbanne, France
Institut National de la Recherche Agronomique, INA P-G, 75231 Paris 5, France
Studies in invertebrates have led to the identification of a number of genes that regulate lifespan, some of which encode components of the insulin or insulin-like signalling pathways. Examples include the related tyrosine kinase receptors InR (Drosophila melanogaster) and DAF-2 (Caenorhabditis elegans) that are homologues of the mammalian insulin-like growth factor type 1 receptor (IGF-1R). To investigate whether IGF-1R also controls longevity in mammals, we inactivated the IGF-1R gene in mice (Igf1r). Here, using heterozygous knockout mice because null mutants are not viable, we report that Igf1r+/- mice live on average 26% longer than their wild-type littermates (P < 0.02). Female Igf1r+/- mice live 33% longer than wild-type females (P < 0.001), whereas the equivalent male mice show an increase in lifespan of 16%, which is not statistically significant. Long-lived Igf1r+/- mice do not develop dwarfism, their energy metabolism is normal, and their nutrient uptake, physical activity, fertility and reproduction are unaffected. The Igf1r+/- mice display greater resistance to oxidative stress, a known determinant of ageing. These results indicate that the IGF-1 receptor may be a central regulator of mammalian lifespan.