ABSTRACT
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 don’t recover with refeeding. Here we find that downregulation of TGFβ signaling bypasses hlh-30 collapse, 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-30 loss 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.
Competing Interest Statement
M.S. is shareholder of Senolytic Therapeutics, Inc., Life Biosciences, Inc., Rejuveron Senescence Therapeutics, AG, and Altos Labs, Inc. In the past, M.S. has been consultant (until the end of 2022) of Rejuveron Senescence Therapeutics, AG, and Altos Labs, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
