Emerging evidence suggests that altered myelination is an important pathophysiologic correlate of several neurodegenerative diseases, including Alzheimer and Parkinson's diseases. Thus, improving myelin integrity may be an effective intervention to prevent and treat age-associated neurodegenerative pathologies. It has been suggested that cardiorespiratory fitness (CRF) may preserve and enhance cerebral myelination throughout the adult lifespan, but this hypothesis has not been fully tested. Among cognitively normal participants from two well-characterized studies spanning a wide age range, we assessed CRF operationalized as the maximum rate of oxygen consumption (VO₂max) and myelin content defined by myelin water fraction (MWF) estimated through our advanced multicomponent relaxometry MRI method. We found significant positive correlations between VO₂max and MWF across several white matter regions. Interestingly, the effect size of this association was higher in brain regions susceptible to early degeneration, including the frontal lobes and major white matter fiber tracts. Further, the interaction between age and VO₂max exhibited i) a steeper positive slope in the older age group, suggesting that the association of VO₂max with MWF is stronger at middle and older ages and ii) a steeper negative slope in the lower VO₂max group, indicating that lower VO₂max levels are associated with lower myelination with increasing age. Finally, the nonlinear pattern of myelin maturation and decline is VO₂max-dependent with the higher VO₂max group reaching the MWF peak at later ages. This study provides evidence of an interconnection between CRF and cerebral myelination and suggests therapeutic strategies for promoting brain health and attenuating white matter degeneration.

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