Associations between epigenetic age acceleration and infertility

Abstract

STUDY QUESTION Is the use of ART, a proxy for infertility, associated with epigenetic age acceleration? SUMMARY ANSWER The epigenetic age acceleration measured by Dunedin Pace of Aging methylation (DunedinPoAm) differed significantly between non-ART and ART mothers. WHAT IS KNOWN ALREADY Among mothers who used ART, epigenetic age acceleration may be associated with low oocyte yield and poor ovarian response. However, the difference in epigenetic age acceleration between non-ART and ART mothers (or even fathers) has not been examined. STUDY DESIGN, SIZE, DURATION The Norwegian Mother, Father and Child Cohort Study (MoBa) recruited pregnant women and their partners across Norway at around 18 gestational weeks between 1999 and 2008. Approximately 95 000 mothers, 75 000 fathers and 114 000 children were included. Peripheral blood samples were taken from mothers and fathers at ultrasound appointments or from mothers at childbirth, and umbilical cord blood samples were collected from the newborns at birth. PARTICIPANTS/MATERIALS, SETTING, METHODS Among the MoBa participants, we selected 1000 couples who conceived by coitus and 894 couples who conceived by IVF (n = 525) or ICSI (n = 369). We measured their DNA methylation (DNAm) levels using the Illumina MethylationEPIC array and calculated epigenetic age acceleration. A linear mixed model was used to examine the differences in five different epigenetic age accelerations between non-ART and ART parents. MAIN RESULTS AND THE ROLE OF CHANCE We found a significant difference in the epigenetic age acceleration calculated by DunedinPoAm between IVF and non-ART mothers (0.021 years, P-value = 2.89E−06) after adjustment for potential confounders. Further, we detected elevated DunedinPoAm in mothers with tubal factor infertility (0.030 years, P-value = 1.34E−05), ovulation factor (0.023 years, P-value = 0.0018) and unexplained infertility (0.023 years, P-value = 1.39E−04) compared with non-ART mothers. No differences in epigenetic age accelerations between non-ART and ICSI fathers were found. DunedinPoAm also showed stronger associations with smoking, education and parity than the other four epigenetic age accelerations. LIMITATIONS, REASONS FOR CAUTION We were not able to determine the directionality of the causal pathway between the epigenetic age accelerations and infertility. Since parents’ peripheral blood samples were collected after conception, we cannot rule out the possibility that the epigenetic profile of ART mothers was influenced by the ART treatment. Hence, the results should be interpreted with caution, and our results might not be generalizable to non-pregnant women. WIDER IMPLICATIONS OF THE FINDINGS A plausible biological mechanism behind the reported association is that IVF mothers could be closer to menopause than non-ART mothers. The pace of decline of the ovarian reserve that eventually leads to menopause varies between females yet, in general, accelerates after the age of 30, and some studies show an increased risk of infertility in females with low ovarian reserve. STUDY FUNDING/COMPETING INTEREST(S) This study was partly funded by the Research Council of Norway (Women’s fertility, project no. 320656) and through its Centres of Excellence Funding Scheme (project no. 262700). M.C.M. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement number 947684). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A.

Epigenetic clocks and female fertility timeline: A new approach to an old issue?

“…In a group of n = 181 infertile patients aged 37-39 years, we could confirm that women who subsequently conceived and delivered after ART were epigenetically younger than those who did not (respectively: 36.1 ± 4.2 and 37.3 ± 3.3 years, p < 0.04). In contrast with Monseur et al and Lee et al (Monseur et al, 2020;Lee et al, 2022), we verified that adjusting for the variables that differed between the two groups (AFC, FSH, number of oocytes retrieved) the difference remained statistically significant (p = 0.028). Although these findings should be considered with caution for some aspects (restricted patients' age, choice of the epigenetic model), they suggest that the contribution of epigenetic clocks may not be limited to reflect ovarian reserve.…”

“…Attention should be addressed to the trimester considered. The DNAm GA proposed by Mayne et al was based on I-II trimester healthy pregnancy, that could conceal later adverse events in III trimester (Mayne et al, 2017) while on the opposite way, the clock by Lee et al may encompass Frontiers in Cell and Developmental Biology frontiersin.org some biases due to the training set based on III trimester (Lee et al, 2022). Not at last, as studies in twin pregnancies GA acceleration showed that heritability reached only 57%, environmental factors should be taken into account in the data analysis (Tekola-Ayele et al, 2019).…”

“…In 2022, the role of age acceleration was investigated in a large population of pregnant women and using five different epigenetic aging clocks (DunedinPoAm, PhenoAge, DNAmTL, Hannum clock, Horvath Clock) ( Lee et al, 2022 ). The authors considered a much greater sample size, comparing pregnant women conceiving naturally (n = 1,000) with those who conceived after ART treatment (n = 995 patients) ( Lee et al, 2022 ). They noted that ART mothers aged 0.021 years faster than non-ART ones ( p < 0.03), when the DunedinPoAm clock was adopted.…”

“…They noted that ART mothers aged 0.021 years faster than non-ART ones ( p < 0.03), when the DunedinPoAm clock was adopted. They also found that the etiology of infertility might interplay with epigenetic clock behavior: women with tubal, anovulatory, or idiopathic infertility factor were epigenetically older than the non-ART counterparts ( Lee et al, 2022 ). According to the authors, DunedinPoAm could surpass the other biomarkers in the field of reproductive medicine for its nature of “pace of aging” estimator.…”

“…The authors did not report any information regarding the ovarian reserve, and, by study design, they excluded women with severe infertility that could not be overcome by ART. Finally, data could not be generalized to unpregnant women ( Lee et al, 2022 ).…”