Plasma metabolomic signatures of heterogeneous multimorbidity trajectories in ageing: a population-based cohort study

Age-related disease burden accumulates heterogeneously from later midlife to older age, but the biology underlying these divergent trajectories is poorly understood. We analysed 7199 adults aged 40 years and over in the Tsuruoka Metabolomics Cohort Study, Japan, with baseline fasting plasma metabolomics (94 metabolites measured by capillary electrophoresis-mass spectrometry) and linked health insurance claims. Monthly cumulative Charlson Comorbidity Index scores were constructed from aligned cohort entry to 60 months to capture accumulation of newly documented Charlson conditions after follow-up start. K-means clustering identified six trajectories of claims-recorded disease burden, and ordinal logistic regression related metabolites to ordered trajectory severity with adjustment for demographic and lifestyle factors. Six trajectories ranged from minimal accumulation to rapid progression. Nineteen metabolites were associated with greater trajectory severity after false discovery rate correction. Glutamate showed the strongest positive association (odds ratio, 1.18 per standard deviation; 95% confidence interval, 1.12-1.24), whereas cysteine-glutathione disulfide showed the strongest inverse association (odds ratio, 0.89; 95% confidence interval, 0.86-0.93). Eighteen of these metabolites were also associated with time to first newly documented Charlson disease. Disease-specific analyses linked glutamate to diabetes with complications, mild liver disease, and cerebrovascular disease. Exploratory cluster-specific analyses identified hippurate as a distinctive marker of a late-acceleration trajectory. These findings implicate amino acid metabolism, redox balance, and microbiome-host interactions as candidate biological pathways underlying heterogeneous patterns of age-related disease accumulation, and warrant replication in independent cohorts. These signals may inform biomarker development for accelerated disease-burden accumulation.