Nonninger Tim J, Mak Jennifer, Gerisch Birgit, Ramponi Valentina, Kawamura Kazuto, Ripa Roberto, Schilling Klara, Latza Christian, Kölschbach Jonathan, Serrano Manuel, Antebi Adam
Max Planck Institute for Biology of Ageing, Cologne, Germany.
Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
Nat Aging. 2025 Jun 30. doi: 10.1038/s43587-025-00911-4.
Diapause is a long-lived state of resilience that allows organisms to outlast adversity. Caenorhabditis elegans can endure months in a fasting-induced adult reproductive diapause (ARD) and, upon refeeding, regenerate and reproduce. Here we find that mutants of ARD master regulator hlh-30/TFEB arrest in a senescence-like state during ARD and refeeding, in which germline stem cells are characterized by DNA damage, nucleolar expansion, cell cycle arrest and mitochondrial dysfunction, alongside dysregulated immune and growth metabolic signatures, elevated senescence-associated β-galactosidase and premature aging at the organismal level. Forward genetic screens reveal a TFEB-TGFβ signaling axis that systemically controls diapause, stem cell longevity and senescence, aligning nutrient supply to proper metabolism and growth signaling. Notably, TFEB's vital role is conserved in mouse embryonic and human cancer diapause. Thus, ARD offers a powerful model to study stem cell longevity and senescence in vivo, directly relevant to mammals.
滞育是一种长期的恢复力状态，使生物体能够在逆境中存活更长时间。秀丽隐杆线虫可以在禁食诱导的成虫生殖滞育（ARD）状态下耐受数月，重新进食后能够再生并繁殖。我们发现，ARD主要调节因子hlh-30/TFEB的突变体在ARD和重新进食期间会停滞在类似衰老的状态，其中生殖系干细胞的特征是DNA损伤、核仁扩大、细胞周期停滞和线粒体功能障碍，同时伴有免疫和生长代谢信号失调、衰老相关β-半乳糖苷酶升高以及机体水平的早衰。正向遗传学筛选揭示了一个TFEB-TGFβ信号轴，该信号轴系统地控制滞育、干细胞寿命和衰老，使营养供应与适当的代谢和生长信号相匹配。值得注意的是，TFEB的重要作用在小鼠胚胎和人类癌症滞育中是保守的。因此，ARD为研究体内干细胞寿命和衰老提供了一个强大的模型，与哺乳动物直接相关。
