NHR-8 and P-glycoproteins uncouple xenobiotic resistance from longevity in chemosensory 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 were significantly protected from tunicamycin-induced ER stress. While lifespan extension is dependent on the key longevity factor DAF-16/FOXO, tunicamycin resistance was not. mutants are protected from bacterial pathogens, which is p38 MAP kinase dependent, while TM resistance was independent. Expression of P-glycoprotein (PGP) xenobiotic detoxification genes was elevated in mutants and their knockdown or inhibition with verapamil suppressed tunicamycin resistance. The nuclear hormone receptor was necessary to regulate a subset of PGPs. 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.