Investigating the mediating effect of myokines on exercise-induced cognitive changes in older adults A living systematic review and meta-analysis

Despite strong evidence linking exercise training to cognitive benefits, uncertainty remains regarding the underlying biological mechanisms, with some studies highlighting the need for greater consensus. Muscle-derived exerkines (myokines) are proposed mediators of exercise-induced effects with potential implications for mitigating age-related cognitive decline. This living systematic review and meta-analysis examined randomized controlled trials investigating the effects of exercise on both cognition and any of 1126 potential myokines in individuals aged 50 and older. From 17,177 screened records, 43 studies met inclusion criteria, reporting data on 7 neurotrophic, 11 pro-inflammatory, and 2 anti-inflammatory factors. A three-level meta-analysis revealed significantly improved cognitive performance post-exercise (SMD = 0.579) and elevated neurotrophic factor levels (SMD = 0.427) in exercise groups compared to controls, but no significant changes in pro-inflammatory or anti-inflammatory factor levels. Mediation analysis using meta-analytic structural equation modeling (MASEM) did not detect significant indirect effects of myokines on cognition, with only limited data (9 studies) reporting direct post-test correlations between myokine levels and cognitive outcomes. Exercise improved several cognitive domains and increased certain myokines, particularly BDNF, in older adults. However, current evidence is insufficient to determine whether myokines mediate these benefits, as mediation analyses were limited by small samples, incomplete reporting, and methodological constraints. Future well-powered trials with standardized protocols and comprehensive biomarker reporting are needed to clarify this mechanistic pathway. As a living review, this work will be continuously updated to refine our understanding of whether myokines mediate exercise-induced cognitive benefits in aging populations.