ArticleCell reports2024
LPD-3 as a megaprotein brake for aging and insulin-mTOR signaling in C. elegans.
Article in Cell reports, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 9 citations in OpenAlex.
- Article
- Niclosamide extends health span and reduces frailty by ameliorating mTORC1 hyperactivation in aging models.Journal of advanced research · 2026Article
- Lysosomal control of proteostasis and reproductive capacity by conserved LMD-3 protein inScience advances · 2025Article
- ElixirSeeker: A Machine Learning Framework Utilizing Fusion Molecular Fingerprints for the Discovery of Lifespan-Extending Compounds.Aging cell · 2025Article
- VPS13 and bridge-like lipid transporters, mechanisms, and mysteries.Frontiers in neuroscience · 2025Review
- The role of kinesin-1 in neuronal dense core vesicle transport, locomotion and lifespan regulation in C. elegans.Journal of cell science · 2024Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Insulin-mechanistic target of rapamycin (mTOR) signaling drives anabolic growth during organismal development; its late-life dysregulation contributes to aging and limits 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 C. elegans aging. We find that an agonist insulin, INS-7, is drastically overproduced from early life and shortens lifespan in lpd-3 mutants. LPD-3 forms a bridge-like tunnel megaprotein to facilitate non-vesicular cellular lipid trafficking. Lipidomic profiling reveals increased hexaceramide species in lpd-3 mutants, accompanied by up-regulation of hexaceramide biosynthetic enzymes, including HYL-1. Reducing the abundance of HYL-1, insulin receptor/DAF-2 or mTOR/LET-363, normalizes INS-7 levels and rescues the lifespan of lpd-3 mutants. LPD-3 antagonizes SINH-1, a key mTORC2 component, and decreases expression with age. We propose that LPD-3 acts as a megaprotein brake for organismal aging and that its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways.
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Registered trials
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