Commentary: Exercise as a brake on brain aging—Promise and unresolved questions

Wan and colleagues¹ report a well-designed randomized clinical trial investigating whether 12 months of moderate-to-vigorous aerobic exercise can lower brain-predicted age difference (brain-PAD) in early-to-midlife adults. Their findings are timely and potentially important, showing that exercise produced a modest yet significant reduction in brain-PAD (∼0.95 years vs. controls) alongside improved cardiorespiratory fitness. Nevertheless, several methodological and mechanistic considerations warrant further discussion and may help guide future research in this evolving field.

The between-group difference of ∼0.95 years in brain-PAD, while statistically significant, is modest in absolute terms. For comparison, the Levakov et al.² diet–exercise intervention yielded an ∼8.9-month brain age attenuation, comparable in magnitude, though in a different population and using functional rather than structural connectivity. Whether a sub-1-year difference in brain-PAD translates to meaningful long-term neuroprotection remains unknown. Longer follow-up and larger samples are essential before this effect size can anchor clinical recommendations.

Perhaps the most notable finding was that none of the evaluated biological mediators, including peak volume of oxygen uptake, body composition, blood pressure, or brain-derived neurotrophic factor, significantly explained the reduction in brain-PAD. Rather than representing only a statistical null result, this highlights the current uncertainty surrounding the mechanisms linking exercise to brain aging. Although the authors appropriately acknowledge that the limited sample size (n = 64 exercise and n = 66 control) may have reduced statistical power, the findings may also indicate that additional or alternative mediators warrant investigation.

The field has increasingly turned attention toward neuroinflammatory (interleukin-6 and tumor necrosis factor-alpha), cerebrovascular (neurovascular coupling and cerebral blood flow), epigenetic (DNA methylation aging clocks), and mitochondrial pathways as mediators of exercise-induced brain benefits.3, 4, 5 The absence of these markers from the mediation models is understandable given feasibility constraints, but it means the “black box” between exercise stimulus and brain age reduction remains entirely opaque. This limits translational utility considerably.

BrainageR, the tool employed here, generates brain age estimates from T1-weighted structural magnetic resonance imaging. While validated and widely used,⁶ structural brain age captures morphological change on a timescale that may lag functional adaptation. It is plausible that exercise-induced improvements in cerebral blood flow, white matter microstructure (measurable via diffusion tensor imaging), or resting-state functional connectivity,² precede detectable structural change and may represent more sensitive early markers of benefit. Future trials should incorporate multimodal neuroimaging to address this.

The sample was predominantly White (70.0%), highly educated (mean = 17.23 years), and relatively healthy at baseline.¹ This limits generalizability to populations with elevated cardiometabolic risk, arguably those who would benefit most from intervention. A baseline peak volume of oxygen uptake exclusion above the 75th percentile was appropriate for mechanistic reasons but creates a ceiling effect: fitter individuals show less room for improvement. Whether brain-PAD reductions would be larger in individuals with hypertension, dyslipidemia, or obesity, conditions that independently accelerate brain aging,⁷ remains an open question that stratified or enriched trial designs could address.

The sample was 67.7% female, yet sex was treated as a covariate rather than as a variable of scientific interest.¹ Emerging evidence indicates that brain aging trajectories differ meaningfully by biological sex, particularly across midlife transitions (e.g., perimenopause), which profoundly affect neuroinflammation and brain structure.⁸ Future trials should be powered for sex-stratified analyses or explicitly designed to examine whether exercise-induced brain-PAD reductions differ between males and females.

Future research should move beyond descriptive associations and focus on clarifying the mechanisms underlying exercise-related reductions in brain-PAD by incorporating biomarkers of neurodegeneration, inflammation, cerebrovascular function, and epigenetic aging alongside neuroimaging. Studies are also needed to define dose–response relationships across different exercise modalities and intensities, as well as to determine whether benefits persist over longer follow-up periods. Enriching cohorts with individuals at higher cardiometabolic risk, such as those with hypertension, prediabetes, or elevated body mass index, may help identify populations most likely to benefit. Finally, integrating brain-PAD measures with established dementia biomarkers, including amyloid and phospho-tau markers, could clarify whether exercise-related structural brain changes correspond to reduced Alzheimer’s disease pathology.

Wan and colleagues¹ have made a genuine contribution by demonstrating that a feasible, guideline-aligned exercise program meaningfully shifts a validated biomarker of brain aging in midlife adults. The study is well-conducted, the outcome measure is scientifically defensible, and the preventive timing of the intervention is strategically sound. The challenge now is to move beyond demonstrating that exercise slows brain aging to understanding how—and to identify which individuals benefit most. The gap between effect and mechanism remains the most pressing unresolved question in this growing field.

Declaration of competing interest

The author declares that he has no competing interests.