NHR-49 Acts in Distinct Tissues to Promote Longevity versus Innate Immunity

Abstract

ABSTRACTAging and immunity are inextricably linked and many genes that extend lifespan also enhance immunoresistance. However, it remains unclear if longevity-enhancing factors modulate immunity and longevity by distinct or shared mechanisms. Here, we demonstrate that theCaenorhabditis eleganspro-longevity factor, NHR-49, also promotes resistance againstPseudomonas aeruginosa, but modulates immunity and longevity by spatially and mechanistically distinct mechanisms. Fenofibrate, an agonist of NHR-49’s mammalian functional homolog, PPARα, enhanced worm immunoresistance in an NHR-49-dependent manner. NHR-49 expression is increased by germline ablation, an intervention that extends lifespan, but lowered by pathogen exposure. NHR-49 acted in multiple somatic tissues to promote longevity, whereas, it’s pro-immunity function was mediated by neuronal expression. The canonical NHR-49 target genes,acs-2andfmo-2, were upregulated by germline loss, but infection triggeredfmo-2downregulation andacs-2upregulation. Interestingly, neither gene conferred resistance against Gram-negativePseudomonas, unlike their reported roles in immunity against Gram-positive pathogens. Thus, NHR-49 is differentially regulated by interventions that bring about long-term changes (lifespan extension) vs. short-term stress (pathogen exposure) and in response it orchestrates distinct outputs, including pathogen-specific transcriptional programs. Overall, our study demonstrates the independent control of immunity and longevity by a conserved regulatory protein.