Atlas of genetic architecture and exploratory temporal interaction networks of plasma protein-based organ and system aging

Organ-level investigations provide insights into inter-individual heterogeneity in health and disease, yet aging across organs and systems remains incompletely understood. Leveraging plasma proteomic data from 53,014 UK Biobank participants, we construct 16 organ- and system-specific aging clocks that show 5436 significant associations with 1059 diseases (i.e., 655 incident and 404 prevalent diseases) and widespread responses to 841 diverse environmental factors, highlighting organ-specific and pan-organ patterns. These clocks are benchmarked against two existing models and then externally validated in the China Kadoorie Biobank (n = 3977), supporting their robustness and generalizability. Genetic analyses identify 261 genomic loci associated with these clocks, revealing organ-specific and pleiotropic genetic architectures. Notably, the immune system and liver exhibit the strongest genetic connectivity with other organ systems, closely mirroring their phenotypic correlations. Using longitudinal data from 1006 participants, we apply a multitask Bayesian framework to explore potential temporal interaction networks across organs and systems, identifying temporal precedence of the immune system, liver and stomach, with sex-specific patterns characterized by stronger arterial precedence in females and stomach precedence in males. Together, this study provides a comprehensive atlas integrating genetic, environmental, and interactive insights into multiple plasma protein-based organ and system aging, informing future research on targeted anti-aging strategies. This study provides a comprehensive atlas integrating genetic, environmental, and interactive insights into organ and system aging using multiple plasma protein-based networks, informing future research on targeted anti-aging strategies.