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.

The transcription factor SKN-1, the C. elegans ortholog of mammalian Nrf protein, is a well-known longevity factor, and its activation is observed in several long-lived models. SKN-1 also plays essential roles in xenobiotic and oxidative stress responses. Here, we report deleterious functions of SKN-1 in somatic stress resistance that may impair lifespan. Constitutive SKN-1 activation impairs animal resistance to several stresses, including heat, ER stress and mitochondrial stress, which result from the suppression of DAF-16, another master regulator of longevity. SKN-1 activation abrogates DAF-16 nuclear import and downregulates DAF-16 target genes under stress conditions, while SKN-1 inhibition promotes the expression of DAF-16 targets, even in long-lived mutants. Further, SKN-1 activation induces the expression of vitellogenin proteins, which are required for SKN-1-mediated suppression of DAF-16 and stress resistance. Together, these findings identify detrimental roles for SKN-1 activation in animal health, and more importantly, inspire the rethinking of the complex roles for SKN-1 in aging regulation.