Metabolomic age acceleration and cardiovascular outcomes in a European population-based consortium

Background: Chronological age dominates cardiovascular disease (CVD) risk, yet people of the same age differ in circulating metabolites. We derived a metabolomic age marker and tested whether an older- or younger-looking metabolite profile at a given chronological age was associated with incident CVD. Methods: In the community-based BiomarCaRE case-cohort, Huber LASSO related 138 metabolites to chronological age in 8,946 participants free of atrial fibrillation (AF), heart failure (HF), coronary heart disease (CHD), and stroke, yielding metabolomic age. Age acceleration quantified departure of metabolomic age from expectation for chronological age and sex. Inverse-probability-weighted Cox models related age acceleration to incident CHD, HF, stroke, and AF, adjusted for CVD risk factors. Results: Median age was 59.8 years. A 58-metabolite pattern correlated with chronological age (r = 0.64). Age acceleration related to higher BMI, antihypertensive treatment, alcohol use, and systolic blood pressure and to lower HDL cholesterol and total cholesterol, and inversely to daily smoking (all multivariable p ≤ 0.003). After adjustment for CVD risk factors, each year of age acceleration was associated with HF (hazard ratio [HR] 1.06, 95% CI 1.04–1.08), AF (HR 1.04, 1.03–1.06), and stroke (HR 1.02, 1.01–1.03), but not CHD (HR 1.01, 1.00–1.02). Conclusions: In community-based European cohorts, a targeted metabolomic age marker identified individuals whose blood profile looked older than their chronological age. Age acceleration was associated with incident HF, AF, and stroke after adjustment for classical risk factors, but not with CHD. These findings support metabolomic risk stratification beyond calendar age.

Submitted to the ESC Heart & Stroke 2026 and EuroThrombosis 2026 conference