The Interplay of nutrient cues and growth signaling in diapause reveals novel mechanisms of stem cell longevity and cellular senescence
Year: 2024
Type: dissertation
Abstract: Diapause is a long-lived state of resilience that allows organisms to outlast adversity. C. 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 novel senescence-like state during ARD and refeeding, in which germline stem cells are characterized by DNA damage, nucleolar expansion, cell cycle arrest, and mitochondrial fusion, 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. hlh-30 mutation causes a misalignment between nutrient cues and growth signaling-induced senescence (MINGIS) that abrogates stem cell and organismal longevity, which can be restored by downregulating TGFβ signaling. Notably, TFEB’s vital role is conserved in mouse embryonic and human cancer diapause. Thus, ARD offers a powerful model to rapidly characterize diapause-related regulatory pathways, and study stem cell longevity and senescence in vivo, directly relevant to mammals.
Author: Nonninger, Tim Janis
Language: English
Subfield: Aging
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W6991945924