A primordial TFEB-TGFβ signaling axis systemically regulates diapause and stem cell longevity

Fasting/refeeding enhances animal health and lifespan across taxa. C. elegans can endure months of fasting in adult reproductive diapause (ARD) and upon refeeding, regenerate and reproduce. hlh-30/TFEB is an ARD master regulator whose mutants live mere days in ARD and dont recover with refeeding. Here we find that downregulation of TGF{beta} signaling bypasses hlh-30 collapse, and restores recovery, germline stem cell proliferation and reproductive competence. Upon fasting, HLH-30/TFEB(+) downregulates TGF{beta} 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-30 loss induces a senescent-like DNA damage, immune and growth metabolic signature reversed by inhibiting TGF{beta} signaling. TFEBs role is conserved in mammalian diapause models, including mouse embryonic and human cancer diapause. Thus, TFEB-TGF{beta} axis relays systemic signals matching nutrient supply with growth signaling, to regulate stem cell longevity, senescence and regeneration across species.