Kinome-wide RNAi screening in <i>Caenorhabditis elegans</i> reveals new modulators of insulin signaling and longevity.

The insulin/IGF-I-like signaling (IIS) pathway is a highly conserved signaling cascade that plays a crucial role in regulating longevity across species. Given its significance in aging, identifying novel kinases interacting with the IIS pathway can provide deeper insights into the mechanisms governing longevity. In this study, we performed a targeted RNAi screening of the <i>Caenorhabditis elegans</i> kinome, using dauer formation as a phenotypic readout. We identified several known and novel kinase modulators of the IIS pathway. These hits were enriched with both previously documented and undocumented lifespan regulators. Thermotolerance assays revealed mixed trends, with some kinase inhibitions increasing while others decreasing protection against thermal stress. We observed a positive correlation between thermotolerance and lifespan extension, as well as between dauer formation and lifespan extension, with thermotolerance proving to be a better predictor of longevity. Our findings offer a valuable resource for researchers exploring the IIS pathway and highlight novel, unannotated kinases as potential new therapeutic targets for aging interventions.