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

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.