AI Article Synopsis
- Insulin-mTOR signaling plays a crucial role in growth during development, but its dysregulation can negatively affect aging and lifespan.
- Researchers identified LPD-3 as a megaprotein that helps regulate this signaling during aging, with the insulin agonist INS-7 being linked to shortened lifespans in specific mutants.
- LPD-3 appears to reduce aging effects by interacting with key components of mTOR signaling and influencing lipid metabolism, suggesting that its decline over time contributes to lifespan limitations.
Article Abstract
Insulin-mTOR signaling drives anabolic growth during organismal development, while its late-life dysregulation may detrimentally contribute to aging and limit lifespans. Age-related regulatory mechanisms and functional consequences of insulin-mTOR remain incompletely understood. Here we identify LPD-3 as a megaprotein that orchestrates the tempo of insulin-mTOR signaling during aging. We find that an agonist insulin INS-7 is drastically over-produced in early life and shortens lifespan in mutants, a model of human Alkuraya-Kučinskas syndrome. LPD-3 forms a bridge-like tunnel megaprotein to facilitate phospholipid trafficking to plasma membranes. Lipidomic profiling reveals increased abundance of hexaceramide species in mutants, accompanied by up-regulation of hexaceramide biosynthetic enzymes, including HYL-1 (Homolog of Yeast Longevity). Reducing HYL-1 activity decreases INS-7 levels and rescues the lifespan of mutants through insulin receptor/DAF-2 and mTOR/LET-363. LPD3 antagonizes SINH-1, a key mTORC2 component, and decreases expression with age in wild type animals. We propose that LPD-3 acts as a megaprotein brake for aging and its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9949100 | PMC |
| http://dx.doi.org/10.1101/2023.02.14.528431 | DOI Listing |
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