Epigenetic Aging Signatures in People with Hemophilia

Abstract

Introduction

Hemophilia is a rare X-linked bleeding disorder leading to recurrent hemarthroses, hemophilic arthropathy, and impaired quality of life. A chronic lifelong disease, hemophilia might be associated with accelerated biological aging. Here, we investigated whether biological age derived from epigenetic age estimators differs in hemophilia.

Patients/Methods

We collected blood samples from men with severe (<1 IU/dL; PWSH, n = 20) or mild hemophilia (≥5 IU/dL; PWMH, n = 20), and age-matched healthy male controls (n = 20). DNA methylation of cytosine–phosphate–guanine (CpG) dinucleotides at five genes (ASPA, ITGA2B, PDE4C, FHL2, CCDC10SB) was measured by bisulfite pyrosequencing. Biological age was estimated using two epigenetic aging signatures, each including three CpGs. We investigated differences in biological age and the rate of biological aging between study groups using separate linear regressions on chronological age and study group without and with an interaction, respectively.

Results

Deviations of epigenetic from chronological age were high for both 3-CpG age estimators, with results suggesting systematic overprediction. In both linear regressions using the two 3-CpG estimates, respectively, evidence for a different rate of biological aging in severe hemophilia was weak. The rate of biological aging in PWSH was 0.24 (95% CI, 0.01–0.48) and 0.21 (0.04–0.37) higher compared with PWMH, and 0.05 (−0.19–0.29) and 0.17 (−0.00–0.34) higher compared with healthy controls, respectively. Hemophilic arthropathy was associated with an increased rate of biological aging.

Conclusion

Evidence for a difference in epigenetic aging as reflected by two 3-CpG estimators in severe compared with mild hemophilia or healthy controls was weak.

Keywords

hemophilia - aging - biological clocks - DNA methylation - CpG islands

Authors' Contributions

C.A. conceptualized and designed the study. C.A., D.K., R.V., M.T., and I.P. contributed to the recruitment and acquisition of data. D.K. analyzed the data. C.A. and D.K. interpreted the data and drafted the manuscript. All authors reviewed, edited, and approved the manuscript in its final form.

Publication History

Received: 09 April 2025

Accepted: 24 July 2025

Accepted Manuscript online:
30 September 2025

Article published online:
23 October 2025

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