Abstract
ABSTRACTFasting/refeeding enhances animal health and lifespan across taxa.C. eleganscan endure months of fasting in adult reproductive diapause (ARD) and upon refeeding, regenerate and reproduce.hlh-30/TFEBis an ARD master regulator whose mutants live mere days in ARD and don’t recover with refeeding. Here we find that downregulation of TGFβ signaling bypasseshlh-30collapse, and restores recovery, germline stem cell proliferation and reproductive competence. Upon fasting, HLH-30/TFEB(+) downregulates TGFβ in sensory neurons, to inhibit Notch and promote reproductive quiescence in the germline. Upon refeeding, these pathways are upregulated to activate stem cells and promote reproduction.hlh-30loss induces a senescent-like DNA damage, immune and growth metabolic signature reversed by inhibiting TGFβ signaling. TFEB’s role is conserved in mammalian diapause models, including mouse embryonic and human cancer diapause. Thus, TFEB-TGFβ axis relays systemic signals matching nutrient supply with growth signaling, to regulate stem cell longevity, senescence and regeneration across species.
Publisher
Cold Spring Harbor Laboratory