Authors: Holzenberger M; Dupont J; Ducos B; Leneuve P; GÃ©loÃ«n A; Even PC; Cervera P; Le Bouc Y
Abstract: 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.Keywords: Aging/genetics; Animals; Blood Glucose/analysis; Cells, Cultured; Female; Fertility/genetics; Fibroblasts; Gene Deletion; Glucose Tolerance Test; Ligands; *Longevity/genetics; Male; Mice; Mice, Knockout; *Oxidative Stress/genetics; Phenotype; Receptor, IGF Type 1/genetics/*metabolism; Sexual Maturation/genetics; Signal Transduction
Date: Dec. 17, 2002
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Holzenberger M, Dupont J, Ducos B, Leneuve P, GÃ©loÃ«n A, Even PC, Cervera P, Le Bouc Y (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421: 182-7.