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bioRxiv · 10.64898/2026.05.13.724957

mTOR regulates longevity through a bile-acid like hormonal mechanism and DHS- 26/DHRS1

Schilling, K.·Antebi, A.·Zaufel, A.·Morris, K. M.·Loehrke, A.·Saini, R.·Knölker, H.-J.·Moustafa, T.
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Abstract

The mTOR pathway is a central regulator of cellular metabolism and growth whose downregulation extends life span across taxa. In C. elegans, mTOR acts cell non-autonomously to influence organismal longevity, yet underlying mechanisms remain elusive. Here, we show that deletion of the TORC1 regulator, raga-1/RRAGA, enhances production of the bile acid-like hormone, dafachronic acid (DA), and extends life span dependent on DA-hormone biosynthetic genes and DA-cognate nuclear hormone receptor DAF-12, a homolog of mammalian farnesoid X receptor (FXR). Through functional genomic screens, we identify the evolutionarily conserved short chain dehydrogenase DHS-26/DHRS1 as a previously uncharacterized downstream regulatory target and effector of the mTOR-steroid axis essential for organismal longevity. Worm DHS-26 is expressed prominently in the canal associated neurons, cells which are essential to growth and development, suggesting a neuroendocrine mechanism. Murine DHRS1 also exhibits regulation by mTOR signaling and nuclear receptor FXR suggesting that the mTOR-DHS-26/DHRS1 axis is evolutionarily conserved. These findings suggest that mTOR signaling systemically impacts metazoan longevity through the regulation of bile acid-like hormone availability and nuclear receptor signal transduction.

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Schilling, K., Antebi, A., Zaufel, A., Morris, K. M., Loehrke, A., Saini, R., Knölker, H.-J., Moustafa, T.. 2026-05-17. mTOR regulates longevity through a bile-acid like hormonal mechanism and DHS- 26/DHRS1. https://doi.org/10.64898/2026.05.13.724957

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