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

Nature volume 421, pages 182–187 (2003)Cite this article

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 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.

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Figure 1: IGF-1R gene targeting, receptor expression and growth phenotype.
Figure 2: Lifespan extension in Igf1r+/- mice with respect to Igf1r+/+ (WT) mice.
Figure 3: Glucose tolerance and energy metabolism in Igf1r+/- mice.
Figure 4: Mutants show normal fertility and are resistant to oxidative stress.
Figure 5: Lack of IGF-1R reduces activation of major intracellular signalling pathways in cultured MEFs.

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Acknowledgements

We thank P. Monget for contributions to the experimental design; N. R. Holzenberger for assistance with metabolic and growth studies; G. Hamard for help with MEFs; J. Sappa for language revision; F. Veinberg for blood biochemistry; and P. Casanovas and M.-C. Samson for animal care. MENRT sponsored this study with a grant to M.H. and Y.L.B. We thank D. LeRoith for support to J.D.

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Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale U515, Hôpital Saint-Antoine, 75571 12, Paris, France

    Martin Holzenberger, Bertrand Ducos, Patricia Leneuve & Yves Le Bouc

  2. Service d'Anatomie et de Cytologie Pathologiques, Hôpital Saint-Antoine, 75571 12, Paris, France

    Pascale Cervera

  3. Institut National de la Recherche Agronomique, 37380, Nouzilly, France

    Joëlle Dupont

  4. Institut National de la Santé et de la Recherche Médicale U352, INSA, 69621, Villeurbanne, France

    Alain Géloën

  5. Institut National de la Recherche Agronomique, INA P-G, 75231 5, Paris, France

    Patrick C. Even

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  1. Martin Holzenberger
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Correspondence to Martin Holzenberger.

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Holzenberger, M., Dupont, J., Ducos, B. et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187 (2003). https://doi.org/10.1038/nature01298

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