NHR-8 and P-glycoproteins uncouple xenobiotic resistance from longevity in chemosensory <i>C. elegans</i> mutants.

Abstract

Longevity is often associated with stress resistance, but whether they are causally linked is incompletely understood. Here we investigate chemosensory-defective <i>Caenorhabditis elegans</i> mutants that are long-lived and stress resistant. We find that mutants in the intraflagellar transport protein gene <i>osm-3</i> were significantly protected from tunicamycin-induced ER stress. While <i>osm-3</i> lifespan extension is dependent on the key longevity factor DAF-16/FOXO, tunicamycin resistance was not. <i>osm-3</i> mutants are protected from bacterial pathogens, which is <i>pmk-1</i> p38 MAP kinase dependent, while TM resistance was <i>pmk-1</i> independent. Expression of P-glycoprotein (PGP) xenobiotic detoxification genes was elevated in <i>osm-3</i> mutants and their knockdown or inhibition with verapamil suppressed tunicamycin resistance. The nuclear hormone receptor <i>nhr-8</i> 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 <i>osm-3</i> mutants.