Abstract
Aging clocks quantify biological aging and help characterize individual health status. What protein interactions are important for accurate aging clocks, and are they zeroth-order or higher-order? Addressing these questions requires learning from large molecular datasets distributed across medical centers, where privacy constraints prevent centralized data sharing. Federated learning offers a natural solution but faces four challenges in this setting: limited local sample sizes, sparse and directional inter-center trust, the need to retain discriminative age prediction while supporting interpretation, and model drift and forgetting under heterogeneous cross-center data. We propose TNFL, a trust-network-based federated learning framework that progressively propagates models along directed pairwise trust relations without centralized aggregation. TNFL combines an age-aware mixture-of-experts model with generative replay to preserve previously learned information and reduce forgetting and drift. Experiments across multiple molecular datasets show that TNFL enables effective aging-clock prediction with limited local data, provides interpretable age-dependent prediction patterns, and maintains stable performance across interaction orders. To investigate the biological questions, we analyze TNFL-identified pairwise protein interactions and their higher-order organization through functional and network analyses. The identified interactions repeatedly form coordinated higher-order subnetworks spanning multiple aging-related biological systems, with several proteins recurring across subnetworks. These findings suggest that TNFL captures molecular relationships beyond isolated pairwise associations and reveals coherent higher-order biological organization associated with aging.
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URL
https://arxiv.org/abs/2609.10108
