PR002813 (Project)

Description:Chronic inflammation is a hallmark of aging, but the underlying mechanisms of how inflammatory signaling drives aging remain unclear. Inflammation is in part controlled by the lipid-based eicosanoid signaling cascade consisting of three branches defined by their lipid-metabolizing enzymes, namely cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450 (CYPs) enzymes. In an unbiased small molecule screen for lifespan extension in C. elegans, we identify the sulfonyl fluoride SF-3 and show it to extend lifespan by inhibiting soluble epoxide hydrolase 1 (CEEH-1) of C. elegans, a key enzyme in the CYP branch of the eicosanoid cascade. In C. elegans, the hydrolysis of epoxy fatty acids by CEEH-1 generates toxic dihydroxyeicosanoids (DiHETs) that shorten lifespan by the chronic activation of the ATF-6 arm of the UPRER. Our results causally link the CYP branch of the eicosanoid cascade to aging via the hydrolysis of epoxides into DiHETs, some of which are toxic and thus provide a mechanism for how inflammatory signaling drives aging.