Longevity effect of IGF‐1R+/− mutation depends on genetic background‐specific receptor activation |
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Authors: | Zayna Chaker Philippe Lacube Joëlle Dupont Martin Holzenberger |
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Institution: | 1.INSERM, Hôpital Saint-Antoine, Paris, 75012, France;2.Université Pierre et Marie Curie, UPMC, Paris, 75005, France;3.Faculté de Médecine, Université Paris Descartes, Paris, 75006, France;4.INRA UMR7247, Nouzilly, 37380, France;5.CNRS UMR6175, Nouzilly, 37380, France;6.Université François Rabelais, Tours, 37041, France |
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Abstract: | 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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Keywords: | Genetic background gene knockout IGF‐I
IRS
lifespan stress resistance |
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