Nurpudji Astuti Taslim, Jeremy Nicolas Sibarani, Ricky Indra Alfaray, Nelly Mayulu, Arifa Mustika, Dian Aruni Kumalawati, Happy Kurnia Permatasari, Raymond Rubianto Tjandrawinata, Fahrul Nurkolis
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. © 2026 by the authors.
Division of Clinical Nutrition, Department of Nutrition, Faculty of Medicine, Hasanuddin University, Makassar, 90245, Indonesia; Faculty of Medicine, Universitas Airlangga, Surabaya, 60131, Indonesia; Medical Research Center of Indonesia, Surabaya, 60281, Indonesia; Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, 60131, Indonesia; Department of Nutrition, Faculty of Health Science, Muhammadiyah Manado University, Manado, 95249, Indonesia; Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine, Universitas Airlangga, Surabaya, 60131, Indonesia; Department of Biomedical Sciences, Faculty of Sciences and Technology, State Islamic University of Sunan Kalijaga, UIN Sunan Kalijaga, Yogyakarta, 55281, Indonesia; Department of Biochemistry and Biomolecular, Faculty of Medicine, Brawijaya University, Malang, 65145, Indonesia; Center for Pharmaceutical and Nutraceutical Research and Policy, Atma Jaya Catholic University of Indonesia, Jakarta, 12930, Indonesia; Institute for Research and Community Service, State Islamic University of Sunan Kalijaga (UIN Sunan Kalijaga), Yogyakarta, 55281, Indonesia
