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 additively extended lifespan, preserved reproductive capacity, and improved locomotor function. Targeted metabolomics with stable isotope tracing revealed increased mitochondrial TCA cycle flux and enhanced gut redox homeostasis, suggesting these as central metabolic features. Notably, Lactiplantibacillus plantarum was found to be associated with the observed benefits, and recolonization experiments suggested that it partially accounts for the benefits conferred by MR-Tau combined with exercise, supporting a causal but partial role. Together, these findings support a "nutrition-behavior-microbiota" framework that uncouples the traditional trade-off between lifespan and functional health, offering new perspectives for promoting healthy aging.