Longevity is often associated with stress resistance, but whether they are causally linked is incompletely understood. Here we investigate chemosensory defective Caenorhabditis elegans mutants that are long-lived and stress resistant. We find that mutants in the intraflagellar transport protein gene osm-3 are completely protected from tunicamycin (TM)-induced ER stress. While osm-3 lifespan extension is fully dependent on the key longevity factor DAF-16/FOXO, TM resistance is not. osm-3 mutants are protected from bacterial pathogens, which is fully pmk-1 p38 MAP kinase dependent. Transcriptomic analysis revealed enhanced expression of P-glycoprotein xenobiotic detoxification genes in osm-3 mutants and chemical inhibition of P-glycoproteins with verapamil suppressed TM resistance. Of note, the nuclear hormone receptor nhr-8 is necessary and sufficient to regulate P-glycoproteins and TM 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 osm-3 mutants.

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