Universität zu Köln

Schilling, Klara (2026). Regulation of longevity by an mTOR/steroid signaling axis in C. elegans. PhD thesis, Universität zu Köln.

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Abstract

The mTOR pathway is a key central regulator of cellular growth and aging. A modest inhibition of mTOR slows organismal growth and promotes longevity across taxa, including C. elegans. Work in mammalian systems suggests that the steroid cholesterol is a positive regulator of mTOR and that mTOR in turn regulates bile acid homeostasis in mice. Worms synthesize cholesterol-derived bile acid-like steroids called dafachronic acids (DAs), which bind to the steroid receptor transcription factor DAF-12, the C. elegans homolog of the mammalian vitamin D, liver X, and farnesoid X receptors. DAF-12 serves as a molecular switch regulating developmental timing, dauer formation, as well as gonad signaling mediated longevity. We therefore hypothesized that daf-12/DA signaling might interact with mTOR signaling, using raga-1 mutants as a genetic model of reduced TORC1. We found that null mutations of daf-12 as well as mutations in DA biosynthetic enzymes abolished raga-1 longevity, suggesting that reduced mTOR signaling acts through DA/DAF-12 signaling to extend life span. Consistently, with the idea of a regulatory cascade, we found that raga-1 mutation resulted in dramatic upregulation of DA levels to promote DAF-12 transcriptional activity. Furthermore, daf-12 mutation reverses a subset of the transcriptomic and metabolomic changes induced by raga-1 loss. Functional genomic screening of differentially expressed genes from the transcriptome revealed the dehydrogenase dhs-26 (the C. elegans ortholog to the human short-chain dehydrogenase DHRS1), to be required for raga-1 longevity. Our work suggests that dhs-26 plays an integral role in steroid signaling to regulate life span: dhs-26 levels are potently regulated by the positive regulatory arm of steroid/DAF-12 signaling, dhs-26 mutants exhibit decreased 7-DA levels, and raga-1;dhs-26 lifespan can be rescued by 7-DA supplementation. Using single worm proteomics, we identified downstream pathways of DHS-26, including peroxisome and lysosome function, lipid transport, ribosomal biogenesis and oxidative phosphorylation as possible mediators of life span regulation. These findings demonstrate that mTOR and DAF-12 steroid signaling act in a unified pathway to regulate animal longevity through a cell non-autonomous, hormonal mechanism. This cascade engages DHS-26 as a novel regulator of DA levels and DAF-12 activity required for longevity downstream of mTOR signaling. These studies open the possibility that mTOR signaling might act systemically in higher animals through regulation of bile acid-like hormones and nuclear receptor signal transduction.

Item Type:	Thesis (PhD thesis)
Translated title:	Title Language Regulierung der Lebensspanne durch einen mTOR/steroid Signalweg in C. elegans. German
Creators:	Creators Email ORCID ORCID Put Code Schilling, Klara klara.schilling@age.mpg.de UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-803145
Date:	29 April 2026
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Natural sciences and mathematics Life sciences
Uncontrolled Keywords:	Keywords Language Aging English mTOR English steroid English
Date of oral exam:	6 May 2025
Referee:	Name Academic Title Antebi, Adam Professor
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80314