Cardiorespiratory fitness and type 2 diabetes risk: A prospective cohort study with mediation analysis of biological aging in the UK Biobank

AIMS: Higher cardiorespiratory fitness is associated with reduced type 2 diabetes mellitus (T2D) risk, but the underlying mechanisms remain incompletely understood. We investigated whether biological aging mediates the association between maximal oxygen uptake (VO₂max) and incident T2D risk. MATERIALS AND METHODS: This prospective cohort study included 54 418 UK Biobank participants aged 39-70 years without baseline diabetes. VO₂max was estimated using a validated algorithm incorporating resting heart rate, physical activity, age, sex and body mass index. Biological age (BA) and phenotypic age (PhenoAge) were calculated from clinical biomarkers. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for sociodemographic, lifestyle and clinical factors. Linear regression analyses assessed cross-sectional associations between VO₂max and standardised glycaemic and lipid biomarkers. Mediation analysis quantified the proportion of association explained by biological aging measures. RESULTS: During 694 986 person-years of follow-up, 2628 participants developed T2D (incidence rate: 3.78 per 1000 person-years). Compared to the lowest VO₂max quartile, participants in the highest quartile had a 56% lower T2D risk (HR 0.44, 95% CI = 0.39-0.50). Each standard deviation increase in VO₂max was associated with a 28% lower risk (HR 0.72, 95% CI = 0.68-0.76). BA acceleration mediated 8.2% (95% CI = 6.1%-10.8%) and PhenoAge acceleration mediated 9.1% (95% CI = 6.8%-12.1%) of the VO₂max-T2D association. Protective associations were consistent across sex, age, ethnicity and genetic risk subgroups. VO₂max showed strong inverse correlations with glucose (β = -0.32), glycated haemoglobin (β = -0.28), triglycerides (β = -0.31) and a positive correlation with high-density lipoprotein (HDL) cholesterol (β = 0.29). CONCLUSIONS: Higher cardiorespiratory fitness demonstrates robust protective associations against T2D incidence, with biological aging mechanisms partially mediating this relationship.