DNA methylation-based age prediction and telomere length in white blood cells and cumulus cells of infertile women with normal or poor response to ovarian stimulation

Abstract

An algorithm assessing the methylation levels of 353 informative CpG sites in the human genome permits accurate prediction of the chronologic age of a subject. Interestingly, when there is discrepancy between the predicted age and chronologic age (age acceleration or “AgeAccel”), patients are at risk for morbidity and mortality. Identification of infertile patients at risk for accelerated reproductive senescence may permit preventative action. This study aimed to assess the accuracy of the “epigenetic clock” concept in reproductive age women undergoing fertility treatment by applying the age prediction algorithm in peripheral (white blood cells [WBCs]) and follicular somatic cells (cumulus cells [CCs]), and to identify whether women with premature reproductive aging (diminished ovarian reserve) were at risk of AgeAccel in their age prediction. Results indicated that the epigenetic algorithm accurately predicts age when applied to WBCs but not to CCs. The age prediction of CCs was substantially younger than chronologic age regardless of the patient’s age or response to stimulation. In addition, telomeres of CCs were significantly longer than that of WBCs. Our findings suggest that CCs do not demonstrate changes in methylome-predicted age or telomere-length in association with increasing female age or ovarian response to stimulation.

Predict Value of Relative Telomere Length, TERT, and Follicular Fluid Anti-mullerian Hormone Levels for IVF Outcome in Infertile Women

“…It is well established that TL and telomerase activity are known biomarkers for biological aging [29]. Low telomerase activity is associated with unexplained ovarian dysfunction in women [30], and a positive correlation is found between the success of IVF treatment and telomerase activity in granulosa cells [10,31].…”

“…In addition to its established role of compensating for cell replication-dependent telomere shortening, TERT exhibits multiple physiological activities beyond its canonical action. For instance, TERT is shown to modulate mitochondrial and ubiquitin proteasomal function or act as a transcription co-factor [40], to regulate gene expression, to promote cell survival and growth, to protect cells from apoptosis [32], and to display the RNA-dependent RNA polymerase activity [40].A pleiotropic role for TERT in regulating the epigenetic clock [32] and intrinsic DNA methylation age during cell proliferation on advancing cells are also indicated [29].Together, all these TERT effects are actively involved in biological activities, ultimately affecting aging process. In the present study, relative telomere length became shorter while TERT mRNA expression increased with aging in GC.…”

“…These confer the importance of endocrine in ovarian microenvironment. Although the telomere theory of reproductive aging has mostly focused on the effect of shorter telomeres on meiotic errors and higher risk of aneuploidies [29,41], it is also possible that the length of telomeres or telomerase interaction with endocrine in ovarian microenvironment may play a role in ovarian reserve.…”

Epigenetics of Aging and Aging-Associated Diseases

“…Interestingly, the “epigenetic clock” concept of Horvath, has been demonstrated to be very accurate when methylation levels of CpG sites from white blood cells, the central regulators of immune response, were used [ 149 , 150 , 151 ]. These methylation levels were even able to predict mortality [ 152 ].…”

Epigenetic methylation in Eosinophilic Esophagitis: Molecular ageing and novel biomarkers for treatment response

“…30,31 Although EoE is highly associated with atopic illness, epigenetic markers in EoE have not been extensively studied. Methylation markers have been evaluated as predictors of treatment response in other disease processes, [32][33][34] and thus, we hypothesized that DNA methylation markers could serve as a prognostic tool for identifying patients at risk of poor treatment response in the setting of EoE. Furthermore, we hypothesized that molecular or epigenetic age of cells in EoE is accelerated relative to chronological age.…”