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 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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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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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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