Fitness and exercise effects on brain age: A randomized clinical trial

Midlife lifestyle factors, including physical activity, are associated with late-life brain health, yet the role of aerobic exercise on structural brain health in early and mid-adulthood remains poorly understood. This study aimed to examine the effect of aerobic exercise on structural brain age and to explore potential mediators. In a single-blind, 12-month randomized clinical trial, 130 healthy participants aged 26-58 years were randomized into a moderate-to-vigorous intensity aerobic exercise group or a usual-care control group. The exercise group attended 2 supervised 60-min sessions per week in a laboratory setting plus engaged in home-based exercise to achieve 150 min of exercise per week. Brain-predicted age difference (brain-PAD) and cardiorespiratory fitness (CRF) were assessed at baseline and 12 months. Both intention-to-treat (ITT) and completers analyses (including participants who completed post-intervention assessments) were performed. The 130 participants (67.7% female) had an age of 41.28 ± 9.93) years (mean ± SD). At baseline, higher CRF (peak oxygen uptake, VO2peak) was associated with smaller brain-PAD (β = -0.309, p = 0.012). After the intervention, the exercise group showed a decrease in brain-PAD (estimated mean difference (EMD) = -0.60; 95% confidence interval (95%CI): -1.15 to -0.04; p = 0.034) compared to the control group (EMD = 0.35; 95%CI: -0.21 to 0.92; p = 0.217); time × group interaction (between-group difference (BGD) = -0.95; 95%CI: -1.72 to -0.17; p = 0.019). VO2peak improved in the exercise group (EMD = 1.60; 95%CI: 0.29-2.90; p = 0.017) compared to the control group (EMD = -0.78; 95%CI: -2.17 to 0.60; p = 0.265); time × group interaction (BGD = 2.38; 95%CI: 0.52-4.25; p = 0.015). Body composition, blood pressure, and brain-derived neurotrophic factor levels were unaffected. None of the proposed pathways statistically mediated the effect of exercise on brain-PAD. The results from completers were similar. Engaging in 12 months of moderate-to-vigorous exercise reduced brain-PAD in early-to-midlife adults. The pathways by which these effects occur remain unknown.