Epigenetic aging of seminal fluid is associated with inflammation

Male infertility has been a primary cause of global infertility, affecting 8-12% of couples worldwide. Previous studies have shown that semen quality decreases with advanced aging with an increased presence of inflammatory cells. In this study, we examined the DNA methylation of seminal fluid to understand how the methylome changes with age and infertility. We also compare the age associated changes in semen to those observed in buccal swabs in order to characterize differences in epigenetic aging across diverse tissues. We found that infertility associated changes in the DNA methylation of semen are driven by changes in cell composition, while those associated with aging are linked to inflammatory genes. Many age associated sites are demethylated with advanced aging and are associated with the activation of inflammatory pathways. By contrast, we do not observe age associated changes in inflammatory genes in buccal swab methylomes, which instead are characterized by changes to bivalent promoters. Our study suggests that DNA methylation could serve as a biomarker for male infertility assessment in addition to the standard semen analysis. Overall design: To examine the changes in DNA methylation of seminal fluids along with age and to compare across tissues, we collected semen and buccal samples from 83 individuals. We then performed targeted bisulfite sequencing on the samples. Finally, we analyzed the DNA methylation data for all individuals.