Abstract
The growing prevalence of physical and neurological disorders linked to aging poses significant challenges for society. Many of these disorders are closely linked to changes in brain structure and function, highlighting the importance of identifying protective factors that can preserve brain structure in later life and mitigate age-related decline. Physical activity (PA) is consistently linked to physical health and was found to mitigate age-related disorders. However, its effects on markers of brain aging remain inconclusive, partly due to reliance on underpowered studies and self-reported data. We investigated the effects of accelerometer-measured PA and physical fitness on BrainAGE, a machine-learning-derived marker of brain aging, in a large UK Biobank cohort. Using cortical and subcortical neuroimaging-derived features, a BrainAGE model was trained on 21,442 participants (mean absolute error: 3.75 years) and applied to predict BrainAGE for an independent sample of 10,874 participants. Accelerometer-measured moderate-intensity PA, but not self-reported PA, was associated with decelerated brain aging, indicated by a negative BrainAGE. Further, higher hand grip strength, along with lower body mass index (BMI), diastolic blood pressure (DBP), and resting heart rate, was linked to decelerated aging. These fitness measures impacted BrainAGE independently of PA. Additionally, fitness partially accounted for the relationship between PA and BrainAGE. Specifically, BMI, DBP, and resting heart rate showed a significant mediating effect, while grip strength did not. These findings highlight the interplay between PA and fitness in maintaining brain health and provide valuable insights for neuroscience and preventive health measures.