Cytokine signaling through Drosophila Mthl10 ties lifespan to environmental stress

Significance Invertebrates are productive models for understanding basic molecular principles that link cytokine-mediated inflammatory pathways to aging in humans. Here, we use a high-throughput dsRNA screen to determine that the multifunctional Drosophila cytokine, GBP, is a ligand for the hitherto orphan GPCR, Mthl10. Through genetic manipulation of the GBP/Mthl10 axis in larvae and adult flies, we are able to demonstrate how organismal longevity is interconnected to immunological, metabolic, and stress-protective responses. Our results provide a molecular basis for hypothesizing that a successful defense against environmental insults—be they pathogenic inflammation or noninfective challenges—will ultimately reduce lifespan.