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

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 ‐1 R inactivation ( IGF ‐1R +/− ) extends lifespan in female mice on 129/ S v P as 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 ‐1 R +/− mutation in C 57 BL /6J background and investigated the role of insulin/ IGF signaling molecules in strain‐dependent differences. We found significant lifespan extension in female IGF ‐1 R +/− mutants on C 57 BL /6 J background, but the effect was smaller than in 129/ S v P as, suggesting strain‐specific penetrance of longevity phenotypes. Comparing GH / IGF pathways between wild‐type 129/ S v P as and C 57 BL /6J mice, we found that circulating IGF ‐ I and activation of IGF ‐1 R , IRS ‐1, and IRS ‐2 were markedly elevated in 129/ S v P as, while activation of IGF pathways was constitutively low in spontaneously long‐lived C 57 BL /6 J mice. Importantly, we demonstrated that loss of one IGF ‐1 R allele diminished the level of activated IGF ‐1 R and IRS more profoundly and triggered stronger endocrine feedback in 129/ S v P as background than in C 57 BL /6J. We also revealed that acute oxidative stress entails robust IGF ‐1 R pathway activation, which could account for the fact that IGF ‐1 R +/− stress resistance phenotypes are fully penetrant in both backgrounds. Together, these results provide a possible explanation why IGF ‐1 R +/− was less efficient in extending lifespan in C57 BL /6J compared with 129/SvPas.