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Nature 421, 182-187 (9 January 2003) | doi:10.1038/nature01298; Received 4 October 2002; Accepted 18 November 2002; Published online 4 December 2002

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IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice

Martin Holzenberger1, Joëlle Dupont2, Bertrand Ducos1, Patricia Leneuve1, Alain Géloën3, Patrick C. Even4, Pascale Cervera5 & Yves Le Bouc1

  1. Institut National de la Santé et de la Recherche Médicale U515, Hôpital Saint-Antoine, 75571 Paris 12, France
  2. Service d'Anatomie et de Cytologie Pathologiques, Hôpital Saint-Antoine, 75571 Paris 12, France
  3. Institut National de la Recherche Agronomique, 37380 Nouzilly, France
  4. Institut National de la Santé et de la Recherche Médicale U352, INSA, 69621 Villeurbanne, France
  5. Institut National de la Recherche Agronomique, INA P-G, 75231 Paris 5, France

Correspondence to: Martin Holzenberger1 Correspondence and requests for materials should be addressed to M.H. (e-mail: Email: holzenberger@st-antoine.inserm.fr).

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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 pathways1, 2, 3. 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.

  1. Institut National de la Santé et de la Recherche Médicale U515, Hôpital Saint-Antoine, 75571 Paris 12, France
  2. Service d'Anatomie et de Cytologie Pathologiques, Hôpital Saint-Antoine, 75571 Paris 12, France
  3. Institut National de la Recherche Agronomique, 37380 Nouzilly, France
  4. Institut National de la Santé et de la Recherche Médicale U352, INSA, 69621 Villeurbanne, France
  5. Institut National de la Recherche Agronomique, INA P-G, 75231 Paris 5, France

Correspondence to: Martin Holzenberger1 Correspondence and requests for materials should be addressed to M.H. (e-mail: Email: holzenberger@st-antoine.inserm.fr).