Animal studies suggest that the composition of the gut microbiome is at least as important as diet and exercise when it comes to influencing the pace and progression of aging. Both diet and exercise influence the gut microbiome as well – nothing in the body acts in isolation. The composition of the gut microbiome changes with age, and in animal studies approaches that restore a more youthful balance of microbial populations to aged animals improve health and extend life span. Here, researchers review what is known of the links between the metabolites produced by the gut microbiome and the health of aged tissues in the body, with a particular focus on muscle and the brain.
Cognitive frailty, characterized by the coexistence of physical frailty and cognitive impairment, has emerged as a major challenge in aging populations and is closely linked to sarcopenia, neurodegeneration, and chronic inflammation. Increasing evidence suggests that the gut microbiota acts as a central regulator of neuromuscular and neurocognitive aging through the integrated gut-brain-muscle axis.
This review highlights how microbial dysbiosis, reduced short-chain fatty acid (SCFA) production, systemic endotoxemia, and altered microbial metabolites contribute to mitochondrial dysfunction, neuroinflammation, anabolic resistance, and impaired neuroplasticity. Key signaling mediators, including SCFAs, bile acids, tryptophan-derived metabolites, cytokines, and myokines such as irisin, brain-derived neurotrophic factor (BDNF), and cathepsin B, orchestrate bidirectional communication among the gut, skeletal muscle, and brain.
We further discuss the role of exercise-induced microbiota remodeling and muscle endocrine signaling in promoting mitochondrial biogenesis and cognitive resilience. In addition, emerging translational strategies including probiotics, prebiotics, postbiotics, polyphenol-rich functional foods, marine bioactives, and precision nutrition are explored as potential interventions targeting this axis. Collectively, the gut-brain-muscle axis provides a novel systems biology framework for understanding cognitive frailty and developing integrated therapeutic strategies for healthy longevity.
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