TY - JOUR
T1 - Investigating the mediating effect of myokines on exercise-induced cognitive changes in older adults
T2 - A living systematic review and meta-analysis
AU - Vints, Wouter A J
AU - Gökçe, Evrim
AU - Langeard, Antoine
AU - Pavlova, Iuliia
AU - Çevik, Özge Selin
AU - Ziaaldini, Mohammad Mosaferi
AU - Todri, Jasemin
AU - Lena, Orges
AU - Shalom, Salit Bar
AU - Jak, Suzanne
AU - Zorba Zormpa, Ioanna
AU - Karatzaferi, Christina
AU - Levin, Oron
AU - Masiulis, Nerijus
AU - Netz, Yael
AU - PhysAgeNet
PY - 2025/11
Y1 - 2025/11
N2 - 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.
AB - 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.
KW - Aged
KW - Biomarker
KW - Brain
KW - Cognition
KW - Exercise
KW - Muscle
KW - Myokine
KW - Physical activity
U2 - 10.1016/j.neubiorev.2025.106381
DO - 10.1016/j.neubiorev.2025.106381
M3 - (Systematic) Review article
SN - 0149-7634
VL - 178
JO - Neuroscience and Biobehavioral Reviews
JF - Neuroscience and Biobehavioral Reviews
M1 - 106381
ER -