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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Guarente, L. & Kenyon, C. Genetic pathways that regulate ageing in model organisms. Nature 408, 255–262 (2000)
Kenyon, C. A conserved regulatory system for aging. Cell 105, 165–168 (2001)
Gems, D. & Partridge, L. Insulin/IGF signalling and ageing: seeing the bigger picture. Curr. Opin. Genet. Dev. 11, 287–292 (2001)
Kimura, K. D., Tissenbaum, H. A., Liu, Y. & Ruvkun, G. Daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277, 942–946 (1997)
Tissenbaum, H. A. & Ruvkun, G. An insulin-like signaling pathway affects both longevity and reproduction in Caenorhabditis elegans. Genetics 148, 703–717 (1998)
Tatar, M. et al. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292, 107–110 (2001)
Bartke, A. Mutations prolong life in flies; implications for aging in mammals. Trends Endocrinol. Metab. 12, 233–234 (2001)
Clancy, D. J. et al. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292, 104–106 (2001)
Kulkarni, R. N. et al. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96, 329–339 (1999)
Lupu, L., Terwilliger, J. D., Lee, K., Segre, G. V. & Efstratiadis, A. Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev. Biol. 229, 141–162 (2001)
Flurkey, K., Papaconstantinou, J., Miller, R. A. & Harrison, D. E. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc. Natl Acad. Sci. USA 98, 6736–6741 (2001)
Brown-Borg, H. M., Borg, K. E., Meliska, C. J. & Bartke, A. Dwarf mice and the ageing process. Nature 384, 33 (1996)
Coschigano, K. T., Clemmons, D., Bellushi, L. L. & Kopchick, J. J. Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 141, 2608–2613 (2000)
Holzenberger, M. et al. Experimental IGF-I receptor deficiency generates a sexually dimorphic pattern of organ-specific growth deficits in mice, affecting fat tissue in particular. Endocrinology 142, 4469–4478 (2001)
Holzenberger, M. et al. A targeted partial invalidation of the insulin-like growth factor I receptor gene in mice causes a postnatal growth deficit. Endocrinology 141, 2557–2566 (2000)
Liu, J. P., Baker, J., Perkins, A. S., Robertson, E. J. & Efstratiadis, A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75, 59–72 (1993)
Storer, J. B. Longevity and gross pathology at death in 22 inbred mouse strains. J. Gerontol. 21, 404–409 (1966)
Stevens, L. C. & Little, C. C. Spontaneous testicular teratomas in an inbred strain of mice. Proc. Natl Acad. Sci. USA 40, 1080–1087 (1954)
Smith, G. S., Walford, R. L. & Mickey, M. R. Lifespan and incidence of cancer and other diseases in selected long-lived inbred mice and their F1 hybrids. J. Natl Cancer Inst. 50, 1195–1213 (1973)
Whithers, D. J. et al. Irs-2 coordinates IGF-1 receptor-mediated β-cell development and peripheral insulin signalling. Nature Genet. 23, 32–39 (1999)
Hunter, W. S., Croson, W. B., Bartke, A., Gentry, M. V. & Meliska, C. J. Low body temperature in long-lived Ames dwarf mice at rest and during stress. Physiol. Behav. 67, 433–437 (1999)
Finkel, T. & Holbrook, N. J. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247 (2000)
Migliaccio, E. et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309–313 (1999)
Sun, J. & Tower, J. FLP recombinase-mediated induction of Cu/Zn-superoxide dismutase transgene expression can extend the life span of adult Drosophila melanogaster flies. Mol. Cell Biol. 19, 216–228 (1999)
Bartke, A. et al. Extending the lifespan of long-lived mice. Nature 414, 412 (2001)
Kulkarni, R. N. et al. β-cell specific deletion of the IGF-1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter β-cell mass. Nature Genet. 31, 111–115 (2002)
Clancy, D. J., Gems, D., Hafen, E., Leevers, S. J. & Partridge, L. Dietary restriction in long-lived dwarf flies. Science 296, 319 (2002)
Honda, Y. & Honda, S. Oxidative stress and life span determination in the nematode Caenorhabditis elegans. Ann. NY Acad. Sci. 959, 466–474 (2002)
Wolkow, C. A., Kimura, K. D., Lee, M. S. & Ruvkun, G. Regulation of C. elegans life-span by insulinlike signaling in the nervous system. Science 290, 147–150 (2000)
Dupont, J., Karas, M. & LeRoith, D. The potentiation of estrogen on insulin-like growth factor I action in MCF-7 human breast cancer cells includes cell cycle components. J. Biol. Chem. 275, 35893–35901 (2000)
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.
The authors declare that they have no competing financial interests.
About this article
Cite this article
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
Insulin-like growth factor 1 modulates the phosphorylation, expression, and activity of organic anion transporter 3 through protein kinase A signaling pathway
Acta Pharmaceutica Sinica B (2020)
Molecular Therapy (2020)
Doublecortin and IGF-1R protein levels are reduced in spite of unchanged DNA methylation in the hippocampus of aged rats
Amino Acids (2020)
FEBS Letters (2020)
Diphenyl diselenide protects a Caenorhabditis elegans model for Huntington's disease by activation of the antioxidant pathway and a decrease in protein aggregation