NHR-8 regulated P-glycoproteins uncouple xenobiotic stress resistance from longevity in chemosensory C. elegans mutants

Longevity is often associated with stress resistance, but whether they are causally linked is incompletely understood. Here we investigate chemosensory defective mutants that are long-lived and stress resistant. We find that mutants in the intraflagellar transport protein gene are completely protected from tunicamycin-induced ER stress. While lifespan extension is fully dependent on the key longevity factor DAF-16/FOXO, tunicamycin resistance is not. mutants are protected from bacterial pathogens, which is fully p38 MAP kinase dependent. Transcriptomic analysis revealed enhanced expression of P-glycoprotein xenobiotic detoxification genes in mutants and chemical inhibition of P-glycoproteins with verapamil suppressed tunicamycin resistance. Of note, the nuclear hormone receptor is necessary and sufficient to regulate P-glycoproteins and tunicamycin resistance. We thus identify a cell-nonautonomous regulation of xenobiotic detoxification and show that separate pathways are engaged to mediate longevity, pathogen resistance, and xenobiotic detoxification in mutants.