Biological age of the endometrium using DNA methylation

Age has a detrimental effect on reproduction and as an increasing number of women postpone motherhood, it is imperative to assess biological age in terms of fertility prognosis and optimizing fertility treatment individually. Horvath's epigenetic clock is a mathematical algorithm that calculates the biological age of human cells, tissues or organs based on DNA methylation levels. The clock however, was previously shown to be highly inaccurate for the human endometrium, most likely because of the hormonal responsive nature of this tissue. The aim of this study was to determine if epigenetically-based biological age of the human endometrium correlates with chronological age, when strictly timed to the menstrual cycle. Endometrial biopsies from nine women were obtained in two consecutive cycles, both strictly timed to the LH surge (LH+7) and additionally, peripheral whole blood samples were analysed. Using the Illumina HumanMethylation 450K array and Horvath's epigenetic clock, we found a significant correlation between the biological age of the endometrium and the chronological age of the participants, although the endometrial biological age was accelerated by comparison with blood and chronological age. Moreover, similar biological ages were found in pairs of consecutive biopsies, indicating that an endometrial biopsy does not alter the biological age in the following cycle. In conclusion, as long as endometrial samples are timed to the same time point in the menstrual cycle, Horvath's epigenetic clock could be a powerful new biomarker of reproductive aging in the human endometrium.