Advancing understanding of maternal age: correlating epigenetic clocks in blood and myometrium

Advanced maternal age is currently a term defined by chronological age. However, a group of biomarkers known as epigenetic clocks, which can predict morbidity and mortality, has been used to estimate measures of biological aging. Uterine myometrial function during the process of parturition may be influenced by aging, as labor dystocia, unplanned intrapartum cesarean birth, and postpartum hemorrhage are more common in older individuals. The purpose of this study was to evaluate the use of epigenetic clocks in maternal myometrium and blood for predicting age and to evaluate the correlation of epigenetic age between the tissues.

We compared epigenetic age in blood and myometrial samples provided by women undergoing planned cesarean birth at term gestation. Chronological age ranged from 20 to 50 with a median (IQR) age of 35.5(8) years. The MethylationEPIC BeadChip was used to obtain DNA methylation data, and then epigenetic age was calculated using the Horvath, Hannum, GrimAge, and PhenoAge clocks. Spearman correlations of epigenetic age with chronological age were calculated. We tested the relationship of epigenetic age in maternal blood to epigenetic age in myometrium. Age acceleration, for each clock, was also correlated between tissues. Twenty-seven participants provided samples, and 21 matched specimens were included in the final analysis after quality control. Spearman correlation between maternal chronological age and epigenetic age were significant in three of the four clocks (pan-tissue Horvath, Hannum, and GrimAge), for both myometrium and blood samples. Correlations between blood epigenetic age and maternal age ranged from 0.72 to 0.87 (all p < 0.001). Correlations between myometrial epigenetic age and maternal age were also significant (0.62-0.70, p = 0.002), though lower than correlations seen in blood. Maternal blood epigenetic age also correlated with epigenetic age in myometrium with each of these three clocks 0.60 (p = 0.004, Horvath), 0.63 (p = 0.003, Hannum), and 0.80 (p < 0.001, GrimAge). GrimAge age acceleration had the highest correlation between tissues among the clocks (0.49, p = 0.02).

Given the limited sample, this study provides insight into the potential use of epigenetic age derived from blood as a proxy for myometrial epigenetic age, which may be a useful biomarker in estimating myometrial biological age in relationship to myometrial dysfunction. GrimAge outperformed the other tested clocks in terms of concordance of epigenetic age and age acceleration between tissues; however, the Horvath and Hannum clocks may be useful depending on the outcome of interest in pregnancy.