XBP-1 Remodels Lipid Metabolism to Extend Longevity

The endoplasmic reticulum unfolded protein response (UPRER) is a cellular stress response that maintains homeostasis within the secretory pathway, regulates glucose and lipid metabolism, and influences longevity. To ask whether this role in lifespan determination depends upon metabolic intermediaries, we metabotyped C. elegans expressing the active form of the UPRER transcription factor XBP-1, XBP-1s, and found many metabolic changes. These included reduced levels of triglycerides and increased levels of oleic acid (OA), a monounsaturated fatty acid associated with lifespan extension in C. elegans. Here, we show that constitutive XBP-1s expression increases the activity of lysosomal lipases and upregulates transcription of the Δ9 desaturase FAT-6, which is required for the full lifespan extension induced by XBP-1s. Dietary OA supplementation increases the lifespan of wild-type, but not xbp-1s-expressing animals and enhances proteostasis. These results suggest that modulation of lipid metabolism by XBP-1s contributes to its downstream effects on protein homeostasis and longevity.