Gut metabolism links precision nutrition, exercise, and healthspan in Drosophila melanogaster

Longevity-promoting interventions commonly entail functional trade-offs, raising the unresolved question of whether lifespan extension necessarily compromises physiological performance. Here, utilizing a chemically defined diet (CDD) in Drosophila melanogaster, we systematically evaluated a multimodal intervention combining methionine restriction (MR), taurine supplementation (Tau), and moderate exercise. This combinatorial approach synergistically extended lifespan, preserved reproductive capacity, and improved locomotor function. Integrative targeted metabolomics and stable isotope tracing revealed increased mitochondrial tricarboxylic acid (TCA) cycle flux and enhanced redox homeostasis in the gut as central metabolic features. Notably, Lactobacillus plantarum was identified as a key microbial mediator responsive to dietary and behavioral stimuli, potentially coordinating host energy metabolism and maintaining physiological integrity. Together, these observations outline a "nutrition-behavior-microbiota" framework that uncouples the traditional trade-off between lifespan and functional health, offering new perspectives for promoting healthy aging.