Immune Aging is an Independent Risk Factor for Cardiovascular Disease

Feldman, E.; Santana, E. J.; Celestin, B.; Golden, N.; Bagherzadeh, S.; Maysel, S.; Mathi, K.; Short, S.; Caroll, M.; Sullivan, S. S.; Lukacisin, M.; Ji, X.; Klein, Y.; Caspi, O.; Nguyen, P.; Fearon, W. F.; Kim, B.; Shah, S.; Mahaffey, K. W.; Maecker, H. T.; Davis, M. M.; Milman, N.; Few-Cooper, T. J.; Haddad, F.; Shen-Orr, S. S.

doi:10.64898/2026.05.18.725733

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bioRxiv · 10.64898/2026.05.18.725733

Immune Aging is an Independent Risk Factor for Cardiovascular Disease

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Abstract

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.

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Feldman, E., Santana, E. J., Celestin, B., Golden, N., Bagherzadeh, S., Maysel, S., Mathi, K., Short, S., Caroll, M., Sullivan, S. S., Lukacisin, M., Ji, X., Klein, Y., Caspi, O., Nguyen, P., Fearon, W. F., Kim, B., Shah, S., Mahaffey, K. W., Maecker, H. T., Davis, M. M., Milman, N., Few-Cooper, T. J., Haddad, F., Shen-Orr, S. S.. 2026-05-20. Immune Aging is an Independent Risk Factor for Cardiovascular Disease. https://doi.org/10.64898/2026.05.18.725733

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