High cardiorespiratory fitness is associated with younger brain age: the role of systemic inflammation

• High Cardiorespiratory fitness (CRF) is associated with a younger brain age, especially among males and people with central obesity. • Systemic inflammation partly mediates the CRF-brain aging association. • CRF could be used as a pre-clinical indicator of brain aging. • Preserving cardiovascular health may support brain health through anti-inflammatory pathways, with males and individuals with central obesity potentially benefiting more. To examine the relationship between cardiorespiratory fitness (CRF) and brain aging, and the extent to which this is mediated by systemic inflammation. This study included 4,770 adults from the UK Biobank (mean age: 55.37 ± 7.50 years) at baseline, who underwent structural and functional brain magnetic resonance imaging (MRI) at a follow-up examination conducted an average of 8.9 years after the baseline. CRF was estimated from a 6-minute submaximal exercise test on a stationary bike and expressed as age- and sex-standardized tertiles (i.e., low, moderate, and high). Brain age was estimated using a machine learning model based on 1,079 brain MRI phenotypes. Low-grade inflammation was quantified using four inflammatory biomarkers with standard assessment. Data were analyzed using linear regressions and generalized structural equation models. At baseline, standardized CRF z‑scores ranged from −2.59 to 26.60. Compared to participants with low CRF, those with high CRF had younger brain age than chronological age ( β = − 0.52 [95 % confidence interval: −0.92, −0.13]). High CRF was associated with lower inflammation ( β = − 2.75 [−3.16, −2.34]), which in turn was associated with younger brain age ( β = − 0.05 [−0.08, −0.02]). In the mediation analysis, lower inflammation mediated 20.65 % ( P = 0.005) of the associations between high CRF and younger brain age. High CRF is associated with a younger brain age, and lower systemic inflammation partly mediates this association.