AI Insight
This study demonstrates that downregulation of the mTOR pathway in C. elegans enhances production of a bile acid-like hormone called dafachronic acid (DA), which extends lifespan through the nuclear hormone receptor DAF-12, a homolog of the mammalian farnesoid X receptor (FXR). Using functional genomic screens, the researchers identified a conserved enzyme, DHS-26/DHRS1, as a key downstream effector of this mTOR-steroid signaling axis, expressed notably in neurons associated with growth regulation. Importantly, the mouse equivalent of this enzyme (DHRS1) also responds to mTOR signaling and FXR activity, suggesting this mechanism is evolutionarily conserved across species.
Why it matters
These findings point toward a hormonal and neuroendocrine mechanism by which mTOR signaling influences aging across species, potentially opening new avenues for longevity-related therapeutic interventions targeting bile acid signaling or the mTOR-DHRS1 axis in mammals, including humans.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.
Source: mTOR regulates longevity through a bile-acid like hormonal mechanism and DHS- 26/DHRS1