Distance of covariance (DISCO), a novel measure of network homeostatic dysregulation, reveals organ system interconnections underlying mortality and disease risk

Aging manifests as the progressive declines of homeostatic resilience and repair mechanisms, marked by dysregulations across systems and increasing individual heterogeneity. However, the breadth of measures of homeostatic dysregulation remains underexplored. Here, we introduce DISCO as a novel measure of homeostatic dysregulation, integrating clinical, proteomics, metabolomics, and microbiomes data. DISCO demonstrated moderate correlation with chronological age but robustly predicted mortality, frailty, and chronic disease risk, outperforming Mahalanobis distance in health outcome prediction, comparable to the best epigenetic clocks. Organ/tissue-specific DISCO analysis revealed limited organ-disease specificity, suggesting systemic rather than localized dysregulation drives health decline. Network analysis identified aging-associated proteins as central hubs strongly linked to DISCO scores; further, organ-level DISCO metrics most predictive of age and outcomes were also central within biological networks. Collectively, DISCO emerges as a validated measure of whole-body homeostatic dysregulation, providing a tool for aging risk stratification and insights into systemic aging mechanisms.