Cell nonautonomous roles of NHR‐49 in promoting longevity and innate immunity

Aging and immunity are inextricably linked and many genes that extend life span also enhance immunoresistance. However, it remains unclear whether longevity‐enhancing factors modulate immunity and longevity by discrete or shared mechanisms. Here, we demonstrate that the Caenorhabditis elegans pro‐longevity factor, NHR‐49, also promotes resistance against Pseudomonas aeruginosa but modulates immunity and longevity distinctly. NHR‐49 expression increases upon germline ablation, an intervention that extends life span, but was lowered by Pseudomonas infection. The immunosusceptibility induced by nhr‐49 loss of function was rescued by neuronal NHR‐49 alone, whereas the longevity diminution was rescued by expression in multiple somatic tissues. The well‐established NHR‐49 target genes, acs‐2 and fmo‐2, were also differentially regulated following germline elimination or Pseudomonas exposure. Interestingly, neither gene conferred immunity toward Gram‐negative Pseudomonas, unlike their known functions against gram‐positive pathogens. Instead, genes encoding antimicrobial factors and xenobiotic‐response proteins upregulated by NHR‐49 contributed to resistance against Pseudomonas. Thus, NHR‐49 is differentially regulated by interventions that bring about long‐term changes (life span extension) versus short‐term stress (pathogen exposure) and in response it orchestrates discrete outputs, including pathogen‐specific transcriptional programs. Longevity and immune health are intimately connected, but it is unclear whether the two can be genetically uncoupled. This study shows that a worm transcription factor, NHR‐49, promotes both longevity and immunity distinctly. NHR‐49 expression in neurons is critical for immunoresistance, whereas its presence in multiple tissues can improve longevity. It controls the production of antibacterial proteins to combat infection and alters fat breakdown to increase life span.