Abstract
Aerobic exercise mitigates age-related intestinal senescence through gut microbiota modulation, but the underlying mechanism has remained unclear. In this study, we performed 16S rRNA sequencing of gut contents from young, old, and old exercise C57BL/6J mice to assess exercise-induced alterations in microbiota community structure. Differential taxa analyses were applied to reveal age-associated bacterial signatures, gut barrier integrity, and systemic inflammation. Additionally, untargeted metabolomic profiling was employed to characterize gut metabolic profiles and reveal the key pathways through differential metabolite enrichment analyses. Aging significantly exacerbated the senescence-associated secretory phenotypes and the overgrowth of pathogenic bacteria in mice. However, aerobic exercise ameliorated these age-related deteriorations, restored gut microbial homeostasis, and reduced intestinal permeability. Notably, exercise intervention led to a significant increase in Akkermansia abundance in feces, establishing this mucin-degrading bacterium as a prominent exercise-responsive microbe. Metabolomic profiling identified eicosanoid metabolism as the most significantly perturbed pathway, and chronic exercise was found to regulate 14,15-Dhet levels. Our multi-omics integration confirmed that exercise is a potent modulator of the gut-microbiota-metabolite axis during aging. Elucidating the "Akkermansia-eicosanoid signaling" axis provided mechanistic insights into how exercise promotes healthy aging, identifying novel targets for anti-aging strategies via microbiota.