Potential effects of β-hydroxy-β-methylbutyrate and exercise on brain aging and age-related disorders: implications for immunometabolic regulation and muscle-brain-immune crosstalk.

β-Hydroxy-β-methylbutyrate (HMB), a bioactive leucine metabolite, has emerged as a potentially valuable nutritional compound with effects extending beyond skeletal muscle metabolism toward systemic immunometabolic regulation. This review summarizes evidence from 24 experimental and clinical studies regarding the potential relevance of HMB to brain aging and age-related disorders, with emphasis on mitochondrial regulation, inflammatory signaling, redox homeostasis, and exercise-associated adaptations. Most studies report improvements in muscle strength, physical performance, and functional capacity, frequently without substantial increases in muscle mass. Proposed mechanisms include modulation of protein turnover, attenuation of apoptosis, regulation of autophagy, and preservation of mitochondrial dynamics. Emerging evidence also suggests that HMB may influence inflammatory gene expression, oxidative stress pathways, and immune-related signaling. However, direct central nervous system (CNS)-specific evidence remains limited, as most available findings derive from peripheral, preclinical, or exercise-associated models. Importantly, many included studies employed multicomponent interventions involving resistance training, creatine, vitamin D, or combined nutritional supplementation, making it difficult to isolate HMB-specific effects. Exercise itself appears to remain the principal driver of mitochondrial adaptation, inflammatory modulation, and functional improvement, whereas HMB demonstrates primarily adjunctive or context-dependent effects. Consequently, HMB should presently be regarded as a potential indirect modulator of muscle-brain-immune interactions during aging rather than a definitively established neuroactive compound. Further mechanistically rigorous and CNS-focused studies are required.