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 were significantly protected from tunicamycin-induced ER stress. While osm-3 lifespan extension is dependent on the key longevity factor DAF-16/FOXO, tunicamycin resistance was not. osm-3 mutants are protected from bacterial pathogens, which is pmk-1 p38 MAP kinase dependent while TM resistance was pmk-1 independent. Expression of P-glycoprotein (PGP) xenobiotic detoxification genes was elevated in osm-3 mutants and their knockdown or inhibition with verapamil suppressed tunicamycin resistance. The nuclear hormone receptor nhr-8 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 osm-3 mutants.

27Longevity is often associated with stress resistance, but whether they are causally 28 linked is incompletely understood. Here we investigate chemosensory defective 29Caenorhabditis elegans mutants that are long-lived and stress resistant. We find that 30 mutants in the intraflagellar transport protein gene osm-3 are completely protected 31 from tunicamycin-induced ER stress. While osm-3 lifespan extension is fully dependent 32 on the key longevity factor DAF-16/FOXO, tunicamycin resistance is not. osm-3 33 mutants are protected from bacterial pathogens, which is fully pmk-1 p38 MAP kinase 34 dependent. Transcriptomic analysis revealed enhanced expression of P-glycoprotein 35 xenobiotic detoxification genes in osm-3 mutants and chemical inhibition of P-36 glycoproteins with verapamil suppressed tunicamycin resistance. Of note, the nuclear 37 hormone receptor nhr-8 is necessary and sufficient to regulate P-glycoproteins and 38 tunicamycin resistance. We thus identify a cell-nonautonomous regulation of 39 xenobiotic detoxification and show that separate pathways are engaged to mediate 40 longevity, pathogen resistance, and xenobiotic detoxification in osm-3 mutants. 41

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