Abstract
The contents of numerous membrane lipids change upon ageing. However, it is unknown whether and how any of these changes are causally linked to lifespan regulation. Acyl chains contribute to the functional specificity of membrane lipids. In this study, working with C. elegans, we identified 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 that regulates membrane budding. The reduction in C22 glucosylceramide impairs the clathrin-dependent autophagic lysosome reformation, which subsequently leads to TOR activation and longevity suppression. These findings reveal a mechanistic link between membrane lipids and ageing and suggest a model of lifespan regulation by fatty acid-mediated membrane configuration.
Highlights
The contents of numerous membrane lipids change upon ageing
The C. elegans genome contains three ceramide glycosyltransferase (CGT) genes, cgt-1/2/3 (Fig. 3e), and we found that cgt-3 RNAi (Fig. 4b), but not cgt-1 or cgt-2 RNAi (Supplementary Fig. 4d, e), greatly suppressed gst-4p::GFP expression in glp-1 mutants, indicating that CGT-3 was critical for SKN-1 activation
The lifespanextension effects of germline loss depend on TOR inhibition, which requires normal lysosome homeostasis that is critically regulated by BA, C22 GlcCer, and clathrin
Summary
The contents of numerous membrane lipids change upon ageing. it is unknown whether and how any of these changes are causally linked to lifespan regulation. The reduction in C22 glucosylceramide impairs the clathrin-dependent autophagic lysosome reformation, which subsequently leads to TOR activation and longevity suppression These findings reveal a mechanistic link between membrane lipids and ageing and suggest a model of lifespan regulation by fatty acid-mediated membrane configuration. Lipids that were originally assigned to the germline, accumulate in the soma accompanied with reprogrammed fatty acid metabolism[15,16,17] These accumulated lipids function as energy reserves for somatic maintenance and act as signaling molecules to regulate the conserved longevity transcription factor SKN-1/Nrf and retard the aging process[6,15]. These studies suggest tight links between reproduction, lipid metabolism, and the aging process; the lipid-based signaling through which the germline influences somatic lifespan is not well understood
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