Insulin-mTOR hyperfunction drivesC. elegansaging opposed by the megaprotein LPD-3

AbstractDecreased insulin-mTOR signaling enables exceptional longevity in the nematodeC. elegansby activating geroprotective transcription factors, including DAF-16, SKN-1 and HSF-1. Few studies have examined whether and how increased insulin-mTOR may actively drive organismic aging. Here we show that an agonist insulin INS-7 is drastically over-produced and causes shortened lifespan inlpd-3mutants, aC. elegansmodel of human Alkuraya-Kučinskas syndrome. Lipidomic profiling reveals marked increase in the abundance of hexaceramide species inlpd-3mutants, consistent with up-regulation of the genes encoding biosynthetic enzymes for hexaceramides, including HYL-1 (Homolog ofYeastLongevity). Reducing HYL-1 activity decreases INS-7 levels and rescues the shortened lifespan oflpd-3mutants through InsR/DAF-2 and mTOR/LET-363. We propose that increased insulin signaling exhibits late-life antagonistic pleiotropy and shortens lifespans through sphingolipid-hexaceramide and mTOR regulatory pathways.