Randomized controlled trial of resistance exercise and brain aging clocks

Exercise improves cognition, mental wellbeing, and protects against neurodegeneration. However, most prior neuroscience studies have focused on localized brain changes without quantifying their impact on brain ageing. To quantify the effect of resistance training on brain health using longitudinal assessments. Using resting-state functional magnetic resonance imaging (rs-fMRI) data from 2,433 healthy adults, we trained models to predict brain age and applied them to 309 participants from the Live Active Successful Aging (LISA) randomized trial. Participants in this trial were assigned to one of three groups: heavy-resistance training, moderate-intensity training, or a non-exercise control group. They underwent repeated rs-fMRI and physical fitness assessments at baseline, with follow-up assessments at 1 and 2 years. First, we examined changes in local connectivity between groups. Second, we assessed the impact of resistance training on brain ageing using brain clock models trained on the independent dataset of 2,433 adults. Local analyses revealed increased prefrontal functional connectivity following heavy training, while moderate- and heavy-resistance training significantly reduced brain age (-1.4 to -2.3 years, p_FDR < 0.05). These effects emerged at the whole-brain level, rather than within isolated networks such as the default mode, motor, or cerebellar systems. These findings suggest a hierarchical organization of brain aging, driven by distributed network-level changes and expressed through focal regional patterns. Resistance exercise training decelerates brain ageing, as indexed by brain clocks, reinforcing its role as a preventive strategy for brain health.