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bioRxiv · 10.1101/2023.02.14.528431

Insulin-mTOR hyperfunction drives C. elegans aging opposed by the megaprotein LPD-3

Pandey, T.·Wang, B.·Zu, J.·Deng, H.·Shen, K.·Vale, G.·McDonald, J. G.·Ma, D. K.
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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 C. elegans aging. We find that an agonist insulin INS-7 is drastically over-produced in early life and shortens lifespan in lpd-3 mutants, a C. elegans model of human Alkuraya-Ku[c]inskas 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 lpd-3 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 lpd-3 mutants through insulin receptor/DAF-2 and mTOR/LET-363. LPD-3 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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Pandey, T., Wang, B., Zu, J., Deng, H., Shen, K., Vale, G., McDonald, J. G., Ma, D. K.. 2023-02-15. Insulin-mTOR hyperfunction drives C. elegans aging opposed by the megaprotein LPD-3. https://doi.org/10.1101/2023.02.14.528431

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