Hemophilia is associated with accelerated biological aging.

Abstract

Hemophilia is a rare X-linked bleeding disorder caused by mutations in the F8 or F9 gene (hemophilia A or B), leading to deficient factor VIII or IX proteins, respectively. Hemophilia-related complications caused by bleeding into the joints (the hallmark of hemophilia) and age-related comorbidities occur frequently and impact the functionality and quality of life of persons with hemophilia (PwH). Given the chronic nature of hemophilia, we hypothesized that hemophilia has an association with accelerated biological aging. Therefore, we investigated biological aging biomarkers, i.e., telomere length and mitochondrial DNA (mtDNA) copy number with a quantitative polymerase chain reaction-based assay in PwH (N=99) and age- and sex-matched healthy controls (N=61). The association of telomere length and mtDNA copy number with hemophilia severity was investigated using ordinary least-squares linear regression models allowing for interactions with chronological age. Telomere length (6.09 [interquartile range (IQR), 4.79-7.68] kb vs. 10.07 [IQR, 7.93-12.66] kb; P<0.001) and mtDNA copy number (243.17 [IQR, 206.54-293.79] vs. 495.52 [IQR, 399.60-615.06]; P<0.001) were significantly lower in PwH compared to healthy controls. Persons with severe hemophilia had longer telomere length than those with non-severe hemophilia (6.29 [IQR, 5.36-8.05] kb vs. 5.12 [IQR, 3.97-6.58] kb), while no difference in mtDNA copy number was observed. We observed accelerated biological aging, indicated by shorter telomere length and lower mtDNA copy number, in PwH compared to healthy controls. Interestingly, telomere length shortening was more pronounced in non-severe than in severe hemophilia, which needs further investigations. Further research is needed to understand the underlying mechanisms of biological aging in hemophilia.