E. Feldman, E. J. Santana, B. Celestin, N. Golden, S. Bagherzadeh, S. Maysel, K. Mathi, S. Short, M. Caroll, S. S. Sullivan, M. Lukacisin, X. Ji, Y. Klein, O. Caspi, P. Nguyen, W. F. Fearon, B. Kim, S. Shah, K. W. Mahaffey, H. T. Maecker, M. M. Davis, N. Milman, T. J. Few-Cooper, F. Haddad, S. S. Shen-Orr
Cardiovascular disease remains the leading cause of mortality, yet current clinical predictors miss substantial disease-risk. While the immune system contributes to this residual risk, its complexity has hindered broadly applicable, clinically scalable metrics of immune-state. Here, we establish the prognostic relevance of IMM-AGE, a system-level metric of immune-aging, to cardiovascular disease. We learn reference-free, low-dimensional representations of IMM-AGE across cell, protein, and mRNA measurements, enabling high-fidelity quantification across modalities, blood fractions, and platforms, including standard hospital flow cytometers. Among UK-Biobank participants, 56.9% of IMM-AGE variation remained unexplained by routine clinical measures, and across diverse cohorts totaling ~48,000 individuals, elevated IMM-AGE was independently associated with future cardiovascular risk, intervention outcomes, and mortality. Moreover, incorporation of IMM-AGE into the PREVENT 10-year risk equation significantly improved risk stratification. These findings establish immune-aging as an independent biological dimension of cardiovascular disease-risk and support IMM-AGE as a practical tool for precision risk assessment.