Loehrke, A. | Search bioRxiv

bioRxiv2026

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

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.

genetics↗

bioRxiv2025

Vitamin B12 alleviates Verheij syndrome-like defects via phospholipid remodeling in a C. elegans PUF60 spliceosomopathy model

Verheij syndrome (VRJS) is a rare genetic disorder caused by mutations in the poly(U)-binding splicing factor 60 (PUF60), a core component of the spliceosomal complex. VRJS triggers multiple congenital anomalies, but the underlying pathomechanisms remain poorly understood. Mutation of the Caenorhabditis elegans PUF60 ortholog, rnp-6, recapitulates several hallmarks of VRJS, including growth delay and smaller body size. Here, we demonstrate that developmental defects in rnp-6 mutants are rescued by dietary K12-type Escherichia coli strains. Through complementary genetic screens and multi-omics analyses, we identify vitamin B12 (VB12) as a potent suppressor of these defects, acting via the methionine/S-adenosylmethionine/phosphatidylcholine metabolic axis. Mechanistically, rnp-6 mutation causes aberrant splicing with methionine and phospholipid metabolism-related genes, which cumulatively impair cellular methylation potential, dysregulate phosphatidylcholine metabolism, and induce integrated stress response. We identify intron retention of the nhr-114/HNF4 transcription factor as a primary driver of growth defects, and restoring its splicing robustly suppresses these phenotypes. VB12 supplementation bypasses the aberrant splicing, restores metabolic balance, and activates mTORC1 to rescue developmental phenotypes. Finally, we show that PUF60 deficiency induces aberrant splicing of methionine and phospholipid metabolism-related genes in a human cell line, and is associated with altered plasma methionine and phospholipid levels in VRJS patients. Our findings establish C. elegans as a tractable model for VRJS and uncover SAM/SAH/phospholipid dysregulation as a key mechanism underlying the spliceosomopathy, suggesting VB12 as a potential strategy to mitigate VRJS-related anomalies.

genetics↗