Aging-related cognitive decline is increasingly linked to disruption of the microbiome-gut-brain axis, in which age-associated dysbiosis progressively reduces butyrate production, a short-chain fatty acid and central neuroactive metabolite generated by bacterial fermentation of dietary fiber. Experimental studies indicate that butyrate can influence multiple processes relevant to brain aging, including histone deacetylase activity, neuroinflammatory signaling, microglial phenotypes, blood-brain barrier integrity, synaptic plasticity, and neurogenesis. Through these mechanisms, butyrate may modulate several molecular and cellular processes involved in brain aging, although evidence for direct causal effects in the human brain remains limited. Preclinical studies report neuroprotective effects across several models of aging and neurological disease; however, direct evidence in humans remains limited and largely associative or indirect. Therefore, this review critically synthesizes current evidence on microbiome-derived butyrate in brain aging, encompassing its microbial production and age-related alterations, molecular and cellular mechanisms, associations with neurodegenerative and neuropsychiatric conditions, and emerging strategies for therapeutic modulation and delivery. It examines emerging biotechnological strategies - including prodrug design, nanoparticle- and liposomal-based delivery systems, gut-targeted formulations, and microbiome engineering - all developed to overcome the blood-brain barrier and restore therapeutically relevant butyrate concentrations in the aging brain. By bridging fundamental microbiome biology and translational neuroscience, this review positions butyrate as a mechanistically grounded neurogeroscience effector and charts a roadmap for its application in promoting brain health across the aging continuum.
Gut-Brain Axis