Exercise-regulated bone-brain axis: A novel perspective on age-related cognitive decline

Aging is a significant risk factor for cognitive decline, non-pharmacological interventions such as exercise have demonstrated a protective role in delaying cognitive decline and reducing dementia risk. Exercise activates key signaling pathways, including brain-derived neurotrophic factor and vascular endothelial growth factor, promoting neurogenesis and synaptic plasticity while reducing neuroinflammation. Recent studies have highlighted the bone-brain axis, a bidirectional regulatory network where bone-derived factors, such as osteocalcin and fibroblast growth factor 23 cross the blood-brain barrier, influencing brain function and cognition. Exercise has been shown to enhance the release of bone-derived signals, such as osteocalcin and irisin, further improving cognitive and emotional states, providing new physiological mechanisms for exercise's role in cognitive protection. This review summarizes the progress of research on the bone-brain axis, emphasizing the interplay between bone, brain, and other systems in the context of aging and cognitive decline. Additionally, it explores how exercise can modulate the bone-brain axis to provide potential therapeutic avenues for preventing cognitive decline. Future studies should focus on personalized exercise interventions and combining exercise with other strategies to optimize cognitive health in aging populations.