Effects Of Saturated Very Long Chain Fatty Acid On Lifespan Regulation In C.elegans

The contents of numerous membrane lipids change with aging.However,it is unclear whether and how any of these changes is causally linked to lifespan regulation.Acyl chains contribute to the functional specificity of membrane lipids.Here,working in C.elegans,we identify an acyl chain-specific sphingolipid,C22 glucosylceramide,as a longevity metabolite.Germline deficiency,a conserved lifespan-extending paradigm,induces somatic expression of the fatty acid elongase ELO-3,and behenic acid(22:0)generated by ELO-3 is incorporated into glucosylceramide for lifespan regulation.Mechanistically,C22 glucosylceramide is required for the membrane localization of clathrin,a protein regulating membrane budding.The reduction of C22 glucosylceramide impairs clathrin-dependent autophagic lysosome reformation,which subsequently activates TOR signaling and suppresses longevity.These findings uncover a mechanistic link between membrane lipids and aging,and provide an unprecedented model of lifespan regulation by fatty acid-mediated membrane configuration.