AN INSULIN-LIKE SIGNALING PATHWAY AFFECTS BOTH LONGEVITY AND REPRODUCTION IN CAENORHABDITIS-ELEGANS

Mutations in daf-2 and age-1 cause a dramatic increase in longevity as well as developmental arrest at the dauer diapause stage in Caenorhab ditis elegans. daf-2 and age-1 encode components of an insulin-like si gnaling pathway. Both daf-2 and age-1 act at a similar point in the ge netic epistasis pathway for dauer arrest and longevity and regulate th e activity of the daf-16 gene. Mutations in daf-16 cause a dauer-defec tive phenotype and are epistatic to the diapause arrest and life span extension phenotypes of daf-2 and age-1 mutants. Here we show that mut ations in this pathway also affect fertility and embryonic development . Weak daf-2 alleles, and maternally rescued age-1 alleles that cause life span extension but do not arrest at the dauer stage, also reduce fertility and viability. We find that age-1(hx546) has reduced both ma ternal and zygotic age-1 activity. daf-16 mutations suppress all of th e daf-2 and age-1 phenotypes, including dauer arrest, life span extens ion, reduced fertility, and viability defects. These data show that in sulin signaling, mediated by DAF-2 through the AGE-1 phosphatidylinosi tol-3-OH kinase, regulates reproduction and embryonic development, as well as dauer diapause and life span, and that DAF-16 transduces these signals. The regulation of fertility, life span, and metabolism by an insulin-like signaling pathway is similar to the endocrine regulation of metabolism and fertility by mammalian insulin signaling.