The C. elegans TGF-β Dauer Pathway Regulates Longevity via Insulin Signaling

Background: Previous genetic evidence suggested that the C. elegans TGF-b Dauer pathway is responsible solely for the regulation of dauer formation, with no role in longevity regulation, whereas the insulin/IGF-1 signaling (IIS) pathway regulates both dauer formation and longevity. Results: We have uncovered a significant longevity-regulating activity by the TGF-b Dauer pathway that is masked by an egg-laying (Egl) phenotype; mutants in the pathway display up to 2-fold increases in life span. The expression profiles of adult TGF-b mutants overlap significantly with IIS pathway profiles: Adult TGF-b mutants regulate the transcription of many DAF-16-regulated genes, including genes that regulate life span, the two pathways share enriched Gene Ontology categories, and a motif previously associated with DAF-16regulated transcription (the DAE, or DAF-16-associated element) is overrepresented in the promoters of TGFb regulated genes. The TGF-b Dauer pathway’s regulation of longevity appears to be mediated at least in part through insulin interactions with the IIS pathway and the regulation of DAF-16 localization. Conclusions: Together, our results suggest there are TGF-b-specific downstream targets and functions, but that the TGF-b and IIS pathways might be more tightly linked in the regulation of longevity than has been previously appreciated.