Age-related metabolomic signatures and stroke susceptibility in a population-based cohort

Aging-related metabolic dysregulation and vascular vulnerability contribute substantially to stroke susceptibility, yet subtype-specific metabolic signatures remain incompletely characterized. Employing a nested case-control design within the Taizhou Longitudinal Study, we quantified 296 lipoprotein parameters and 54 metabolites in 1208 stroke-control pairs using nuclear magnetic resonance. Logistic regression estimated subtype-specific associations, and machine learning constructed prediction models for ischemic stroke (IS) and intracerebral hemorrhage (ICH). Distinct metabolic profiles were observed across stroke subtypes. Triglyceride-enriched lipoproteins and several low-molecular-weight metabolites were positively associated with both IS and ICH, whereas apolipoprotein A-related components showed inverse associations, with generally stronger effects observed for IS than for ICH. Age-stratified and interaction analyses revealed age-dependent heterogeneity, especially among histidine and lipoprotein composition measures. To further characterize systemic metabolic vulnerability, we constructed a weighted metabolic risk score (MRS), which was associated with age and statistically accounted for part of the age-stroke association (average causal mediation effects: 0.020 for IS; 0.025 for ICH). MRSs were also positively correlated with age and inflammatory markers, particularly for IS (both P < 0.001). Metabolite-based models improved risk discrimination beyond traditional risk factors for both IS and ICH. These findings identify subtype-specific metabolic signatures of stroke and suggest that circulating metabolomic profiles reflect age-associated metabolic alterations relevant to stroke susceptibility beyond traditional cardiometabolic risk factors.