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

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.

References

  1. 1

    Guarente, L. & Kenyon, C. Genetic pathways that regulate ageing in model organisms. Nature 408, 255–262 (2000)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Kenyon, C. A conserved regulatory system for aging. Cell 105, 165–168 (2001)

    CAS  Article  Google Scholar 

  3. 3

    Gems, D. & Partridge, L. Insulin/IGF signalling and ageing: seeing the bigger picture. Curr. Opin. Genet. Dev. 11, 287–292 (2001)

    CAS  Article  Google Scholar 

  4. 4

    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)

    CAS  Article  Google Scholar 

  5. 5

    Tissenbaum, H. A. & Ruvkun, G. An insulin-like signaling pathway affects both longevity and reproduction in Caenorhabditis elegans. Genetics 148, 703–717 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Tatar, M. et al. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292, 107–110 (2001)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Bartke, A. Mutations prolong life in flies; implications for aging in mammals. Trends Endocrinol. Metab. 12, 233–234 (2001)

    CAS  Article  Google Scholar 

  8. 8

    Clancy, D. J. et al. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292, 104–106 (2001)

    ADS  CAS  Article  Google Scholar 

  9. 9

    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)

    CAS  Article  Google Scholar 

  10. 10

    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)

    CAS  Article  Google Scholar 

  11. 11

    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)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Brown-Borg, H. M., Borg, K. E., Meliska, C. J. & Bartke, A. Dwarf mice and the ageing process. Nature 384, 33 (1996)

    ADS  CAS  Article  Google Scholar 

  13. 13

    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)

    CAS  Article  Google Scholar 

  14. 14

    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)

    CAS  Article  Google Scholar 

  15. 15

    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)

    CAS  Article  Google Scholar 

  16. 16

    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)

    CAS  Google Scholar 

  17. 17

    Storer, J. B. Longevity and gross pathology at death in 22 inbred mouse strains. J. Gerontol. 21, 404–409 (1966)

    CAS  Article  Google Scholar 

  18. 18

    Stevens, L. C. & Little, C. C. Spontaneous testicular teratomas in an inbred strain of mice. Proc. Natl Acad. Sci. USA 40, 1080–1087 (1954)

    ADS  CAS  Article  Google Scholar 

  19. 19

    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)

    CAS  Article  Google Scholar 

  20. 20

    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)

    Article  Google Scholar 

  21. 21

    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)

    CAS  Article  Google Scholar 

  22. 22

    Finkel, T. & Holbrook, N. J. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247 (2000)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Migliaccio, E. et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309–313 (1999)

    ADS  CAS  Article  Google Scholar 

  24. 24

    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)

    CAS  Article  Google Scholar 

  25. 25

    Bartke, A. et al. Extending the lifespan of long-lived mice. Nature 414, 412 (2001)

    ADS  CAS  Article  Google Scholar 

  26. 26

    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)

    CAS  Article  Google Scholar 

  27. 27

    Clancy, D. J., Gems, D., Hafen, E., Leevers, S. J. & Partridge, L. Dietary restriction in long-lived dwarf flies. Science 296, 319 (2002)

    CAS  Article  Google Scholar 

  28. 28

    Honda, Y. & Honda, S. Oxidative stress and life span determination in the nematode Caenorhabditis elegans. Ann. NY Acad. Sci. 959, 466–474 (2002)

    ADS  CAS  Article  Google Scholar 

  29. 29

    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)

    ADS  CAS  Article  Google Scholar 

  30. 30

    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)

    CAS  Article  Google Scholar 

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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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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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