The Nuclear RNAi Pathway Regulates DAF-16/FOXO to Control C. elegans Longevity and Dauer Entry

Caenorhabditis elegans with impaired insulin/IGF-1 receptor signalling (IIS) or with germline ablation live longer and this phenomenon is entirely dependent on the transcription factor DAF-16 - the C. elegans homolog of the class O of the forkhead box transcription factors (FoxO). In a candidate RNAi screen designed to search for new modifiers of DAF-16 function among genes involved in histone modification and/or small RNA-mediated silencing pathways, we found nrde-1, wago-1, and adr-1 as positive regulators of DAF-16. We confirmed by several methods and in different models that DAF-16 translocation to the nucleus and, subsequently, its function is tightly controlled by these genes and narrowed down to components of the NRDE complex and the nuclear RNAi pathway as key DAF-16 modulators. Importantly, we found that the NRDE pathway controls DAF-16-mediated longevity and dauer entry. Our epistasis data indicate that nrde-1 interacts with akt-1 to control lifespan. We also demonstrated that NRDE-1 acts downstream of AGE-1/PI3K and partially requires mTORC2 and AKT-1 to control DAF-16 translocation. These results unveil a mechanism of regulation of dauer formation and longevity in C. elegans via nuclear RNAi-mediated modulation of DAF-16 function in a manner that involves the mTORC2-AKT axis.