Genetic coregulation of age of female sexual maturation and lifespan through circulating IGF1 among inbred mouse strains

We previously reported that mouse strains with lower circulating insulin-like growth factor 1 (IGF1) level at 6 mo have significantly extended longevity. Here we report that strains with lower IGF1 have significantly delayed age of female sexual maturation, measured by vaginal patency (VP). Among strains with normal lifespans (mean lifespan >600 d), delayed age of VP associated with greater longevity (P = 0.015), suggesting a genetically regulated tradeoff at least partly mediated by IGF1. Supporting this hypothesis, C57BL/6J females had 9% lower IGF1, 6% delayed age of VP, and 24% extended lifespan compared with C57BL/6J. C3H/HeJ-Igf1, which carries a C3H/HeJ allele on chromosome (Chr) 10 that increases IGF1. To identify genetic loci/genes that regulate female sexual maturation, including loci that mediate lifespan tradeoffs, we performed haplotype association mapping for age of VP and identified significant loci on Chrs 4 (Vpq1) and 16 (Vpq2 and 3). At each locus, wild-derived strains share a unique haplotype that associates with delayed VP. Substitution of Chr 16 of C57BL/6J with Chr 16 from a wild-derived strain significantly reduced IGF1 and delayed VP. Strains with a wild-derived allele at Vpq3 have significantly extended longevity compared with strains with other alleles. Bioinformatic analysis identified Nrip1 at Vpq3 as a candidate gene. Nrip1(-/-) females have significantly reduced IGF1 and delayed age of VP compared with Nrip1(+/+) females. We conclude that IGF1 may coregulate female sexual maturation and longevity; wild-derived strains carry specific alleles that delay sexual maturation; and Nrip1 is involved in regulating sexual maturation and may affect longevity by regulating IGF1 level.