Multi-Cohort Federated Learning Shows Synergy in Mortality Prediction for MRI-Based and Metabolomics-Based Age Scores.

While biological age scores have been shown to characterize aging by estimating chronological age based on physiological biomarkers, interactions between different age scores are largely unknown. To study this, large-scale multi-modal data are crucial. However, such data are scarce as population-based cohorts are generally restricted in sharing their data. Here, we employ federated learning to study the relationship between the two types of biological age scores: BrainAge based on brain MRI and MetaboAge based on metabolites. Using three large population-based cohorts, we trained a federated deep learning model to estimate BrainAge and compared its performance to models trained in a single cohort. The federated BrainAge model yielded significantly lower error for age prediction across the cohorts than locally trained models. Harmonizing the age interval between cohorts further improved BrainAge accuracy. Subsequently, we compared BrainAge and MetaboAge by performing association analysis and survival analysis for dementia and mortality prediction to further characterize both scores. The association analysis showed a weak association between BrainAge and MetaboAge, while the survival analysis indicated complementary predictive values for the mortality risk of the two scores. Federated learning has been shown to be a valuable technique for enabling the use of research cohorts that are restricted in data sharing. We conclude that BrainAge and MetaboAge act synergetically for the prediction of time to all-cause mortality, and both aging scores capture different aspects of the aging process. Supplementary Information: The online version contains supplementary material available at 10.1007/s41666-025-00208-6.