IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice.
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.
Holzenberger
Martin
M
Institut National de la Santé et de la Recherche Médicale U515, Hôpital Saint-Antoine, 75571 Paris 12, France. holzenberger@st-antoine.inserm.fr
Dupont
Joëlle
J
Ducos
Bertrand
B
Leneuve
Patricia
P
Géloën
Alain
A
Even
Patrick C
PC
Cervera
Pascale
P
Le Bouc
Yves
Y
D000375:Aging / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002478:Cells, Cultured; D005260:Female; D005298:Fertility / Q000235:genetics; D005347:Fibroblasts; D017353:Gene Deletion; D005951:Glucose Tolerance Test; D008024:Ligands; D008136:Longevity / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics; D010641:Phenotype; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D012741:Sexual Maturation / Q000235:genetics; D015398:Signal Transduction
D001786:Blood Glucose; D008024:Ligands; D017526:Receptor, IGF Type 1