Fitness and Exercise Effects on Brain Age: A Randomized Clinical Trial.

Examine the effect of aerobic exercise on structural brain age and explore potential mediators. In a single-blind, 12-month randomized clinical trial, 130 healthy participants aged 26-58 years were randomized into a moderator-to-vigorous intensity aerobic exercise group or a usual-care control group. The exercise group attended 2 supervised 60-minute sessions per week in a laboratory setting plus home-based exercise to achieve 150 minutes of exercise per week. Brain-predicted age difference (brain-PAD) and cardiorespiratory fitness (CRF) were assessed at baseline and 12 months. Intention-to-treat (ITT) and completers analyses were performed. The 130 participants (67.7% female) had a mean (SD) age of 41.28 (9.93) years. At baseline, higher CRF (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% 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=0.22); 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 to 2.90; p=0.017) compared to the control group (EMD=-0.78; 95% CI: -2.17 to 0.60; p=0.26); time×group interaction (BGD=2.38; 95% CI: 0.52 to 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.