Decoding heterogeneous aging clocks and disease risk stratification using a metabolomic foundation model

AO_SCPLOWBSTRACTC_SCPLOWMetabolomic aging clocks estimate biological age by modeling metabolite concentrations, thereby capturing aging signals from healthspan and adverse outcomes. However, existing clocks generally assume homogeneous aging trajectories and yield only a single age acceleration metric, limiting their capacity to capture inter-individual metabolic heterogeneity and characterize nuanced individual-level representations. To address these limitations, we proposed MetFoundation, a metabolomic foundation model pre-trained on nuclear magnetic resonance (NMR) metabolomic profiles from over 430,000 participants in UK Biobank via self-supervised learning. This large-scale pre-training enables MetFoundation to learn a metabolomic representation space that captures the complex, non-linear structure of systemic metabolism as reflected in NMR data. Building on MetFoundation, we developed a mortality-informed metabolomic aging clock by fine-tuning an attached survival module, deriving age acceleration that demonstrates significant associations with multiple age-related diseases and factors. More importantly, we utilized embeddings generated by MetFoundation to identify metabolic subtypes, resulting in 13 distinct subtypes with differential susceptibility profiles for major age-related diseases, particularly dementia and diabetes. This finding empirically demonstrated profound metabolic heterogeneity across populations, persisting even at comparable levels of age acceleration. To enhance clinical applicability, we further employed contrastive learning to distill a lightweight model that approximates the learned metabolomic representation space using only routine blood test measurements as inputs. Both hold-out testing within UK Biobank and the external validation in China Health and Retirement Longitudinal Study replicated similar disease onset patterns across the identified subtypes, underscoring the robust generalizability of MetFoundation and the translational potential of the discovered metabolic subtypes.