Effects of Aging, Estimated Fitness, and Cerebrovascular Status on White Matter Microstructural Health

White matter (WM) microstructural health declines with increasing age, with evidence suggesting that improved cardiorespiratory fitness (CRF) may mitigate this decline. Specifically, higher fit older adults tend to show preserved WM microstructural integrity compared to their lower fit counterparts. However, the extent to which fitness and aging independently impact WM integrity across the adult lifespan is still an open question, as is the extent to which cerebrovascular health mediates these relationships. In a large sample (N = 125, aged 25–72), we assessed the impact of age and estimated cardiorespiratory fitness on fractional anisotropy (FA, derived using diffusion weighted imaging, dwMRI) and probed the mediating role of cerebrovascular health (derived using diffuse optical tomography of the cerebral arterial pulse, pulse-DOT) in these relationships. After orthogonalizing age and estimated fitness and computing a PCA on whole brain WM regions, we found several WM regions impacted by age that were independent from the regions impacted by estimated fitness (hindbrain areas, including brainstem and cerebellar tracts), whereas other areas showed interactive effects of age and estimated fitness (midline areas, including fornix and corpus callosum). Critically, cerebrovascular health mediated both relationships suggesting that vascular health plays a linking role between age, fitness, and brain health. Secondarily, we assessed potential sex differences in these relationships and found that, although females and males generally showed the same age-related FA declines, males exhibited somewhat steeper declines than females. Together, these results suggest that age and fitness impact specific WM regions and highlight the mediating role of cerebrovascular health in maintaining WM health across adulthood.