• Open Access

Longevity effect of IGF-1R+/− mutation depends on genetic background-specific receptor activation

Authors

  • Jie Xu,

    1. INSERM, Hôpital Saint-Antoine, Paris, France
    2. Université Pierre et Marie Curie, UPMC, Paris, France
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    • Both Authors contributed equally to this work.
  • Géraldine Gontier,

    1. INSERM, Hôpital Saint-Antoine, Paris, France
    2. Université Pierre et Marie Curie, UPMC, Paris, France
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    • Both Authors contributed equally to this work.
  • Zayna Chaker,

    1. INSERM, Hôpital Saint-Antoine, Paris, France
    2. Université Pierre et Marie Curie, UPMC, Paris, France
    3. Faculté de Médecine, Université Paris Descartes, Paris, France
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  • Philippe Lacube,

    1. INSERM, Hôpital Saint-Antoine, Paris, France
    2. Université Pierre et Marie Curie, UPMC, Paris, France
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  • Joëlle Dupont,

    1. INRA UMR7247, Nouzilly, France
    2. CNRS UMR6175, Nouzilly, France
    3. Université François Rabelais, Tours, France
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  • Martin Holzenberger

    Corresponding author
    1. INSERM, Hôpital Saint-Antoine, Paris, France
    2. Université Pierre et Marie Curie, UPMC, Paris, France
    • Correspondence

      Martin Holzenberger, Inserm UMR938, Faculté de Médecine, Hôpital Saint-Antoine, 27 rue Chaligny, F-75012 Paris, France. Tel.: +33 (0)140 011 470; fax: +33 (0)140 011 423; e-mail: martin.holzenberger@inserm.fr

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Summary

Growth hormone (GH) and insulin-like growth factor (IGF) signaling regulates lifespan in mice. The modulating effects of genetic background gained much attention because it was shown that life-prolonging effects in Snell dwarf and GH receptor knockout vary between mouse strains. We previously reported that heterozygous IGF-1R inactivation (IGF-1R+/−) extends lifespan in female mice on 129/SvPas background, but it remained unclear whether this mutation produces a similar effect in other genetic backgrounds and which molecules possibly modify this effect. Here, we measured the life-prolonging effect of IGF-1R+/− mutation in C57BL/6J background and investigated the role of insulin/IGF signaling molecules in strain-dependent differences. We found significant lifespan extension in female IGF-1R+/− mutants on C57BL/6J background, but the effect was smaller than in 129/SvPas, suggesting strain-specific penetrance of longevity phenotypes. Comparing GH/IGF pathways between wild-type 129/SvPas and C57BL/6J mice, we found that circulating IGF-I and activation of IGF-1R, IRS-1, and IRS-2 were markedly elevated in 129/SvPas, while activation of IGF pathways was constitutively low in spontaneously long-lived C57BL/6J mice. Importantly, we demonstrated that loss of one IGF-1R allele diminished the level of activated IGF-1R and IRS more profoundly and triggered stronger endocrine feedback in 129/SvPas background than in C57BL/6J. We also revealed that acute oxidative stress entails robust IGF-1R pathway activation, which could account for the fact that IGF-1R+/− stress resistance phenotypes are fully penetrant in both backgrounds. Together, these results provide a possible explanation why IGF-1R+/− was less efficient in extending lifespan in C57BL/6J compared with 129/SvPas.

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