孕妇年龄的增长和与年龄相关的生育能力衰退是现代生殖医学面临的全球挑战。在这方面，临床医生和研究人员特别关注卵巢衰老和激素不足。然而，子宫衰老往往被忽略，大多数生殖医生普遍认为子宫组织的功能随年龄无明显下降。因此目前，现有的解决年龄相关着床率下降的技术主要基于激素补充和卵子捐赠。解决子宫衰老问题可能会导致这些方法的调整。随着衰老信息学的发展，对子宫衰老和减缓其速度的可能性的关注逐渐增加。该理论指出，基因组不稳定性和表观遗传环境的侵蚀是导致大多数细胞和组织功能随年龄下降的重要原因。通过测量表观遗传时钟的滴答声，可以评估这个环境的平滑和组织功能的下降。在本文中，我们探讨了使用这种优雅方法，子宫是否会出现年龄相关的变化。我们分析了内膜中表观时钟的现有数据，强调了提高环境中钟的准确性的方法，推测出可能预测由表观时钟速度改变引起的内膜病变进展的方法，并讨论了减缓这些时钟滴答声的可能性。通过对Medline、PubMed和Google Scholar的搜索，确定了本综述的数据。选择了使用搜索术语“衰老”、“孕妇年龄”、“女性生殖”、“子宫”、“内膜”、“着床”、“蜕化”、“表观遗传时钟”、“生物年龄”、“DNA甲基化”、“生育能力”和“不孕不育”相关文章的参考文献。包括1985年至2022年间发表的95篇英文文章，其中6篇文章描述了使用表观遗传时钟评估子宫内膜的衰老情况。应用Horvath和DNAm PhenoAge表观遗传时钟证明，在内膜中与年龄的时间差异相关性较差。提出了几种方法来增强表观遗传时钟对内膜预测能力。第一种方法是增加训练数据集中的样本数量，如Zang表观遗传钟，或使用更复杂的钟建立算法，如AltumAge表观遗传钟。第二种方法是根据内膜的动态性调整时钟。使用任一方法都显示，在内膜中与年龄的时间差异有很强的相关性，为证明该组织衰老的功能性下降提供了可靠的证据。此外，通过表观遗传时钟估计的年龄加速或减速可能是预测或深入了解各种内膜病理学起源的有希望的工具，包括反复着床失败、癌症和子宫内膜异位症等。最后，有几种减缓或甚至逆转表观遗传时钟的策略，可应用于降低年龄相关子宫损伤的风险。应该考虑到子宫因素，以纠正女性生育能力随着年龄的下降。表观遗传时钟可以用来深入了解各种内膜疾病，提供方法和策略。 © 作者2022年。由牛津大学出版社代表欧洲人类生殖和胚胎学会发表。保留所有权利。请发送邮件至journals.permissions@oup.com索取使用许可。

Rising maternal ages and age-related fertility decline are a global challenge for modern reproductive medicine. Clinicians and researchers pay specific attention to ovarian ageing and hormonal insufficiency in this regard. However, uterine ageing is often left out of the picture, with the majority of reproductive clinicians being close to unanimous on the absence of age-related functional decline in the uterine tissues. Therefore, most existing techniques to treat an age-related decline in implantation rates are based primarily on hormonal supplementation and oocyte donation. Solving the issue of uterine ageing might lead to an adjustment to these methods.A focus on uterine ageing and the possibility of slowing it emerged with the development of the information theory of ageing, which identifies genomic instability and erosion of the epigenetic landscape as important drivers of age-related decline in the functionality of most cells and tissues. Age-related smoothing of this landscape and a decline in tissue function can be assessed by measuring the ticking of epigenetic clocks. Within this review, we explore whether the uterus experiences age-related alterations using this elegant approach. We analyse existing data on epigenetic clocks in the endometrium, highlight approaches to improve the accuracy of the clocks in this cycling tissue, speculate on the endometrial pathologies whose progression might be predicted by the altered speed of epigenetic clocks and discuss the possibilities of slowing down the ticking of these clocks.Data for this review were identified by searches of Medline, PubMed and Google Scholar. References from relevant articles using the search terms 'ageing', 'maternal age', 'female reproduction', 'uterus', 'endometrium', 'implantation', 'decidualization', 'epigenetic clock', 'biological age', 'DNA methylation', 'fertility' and 'infertility' were selected. A total of 95 articles published in English between 1985 and 2022 were included, six of which describe the use of the epigenetic clock to evaluate uterine/endometrium ageing.Application of the Horvath and DNAm PhenoAge epigenetic clocks demonstrated a poor correlation with chronological age in the endometrium. Several approaches were suggested to enhance the predictive power of epigenetic clocks for the endometrium. The first was to increase the number of samples in the training dataset, as for the Zang clock, or to use more sophisticated clock-building algorithms, as for the AltumAge clock. The second method is to adjust the clocks according to the dynamic nature of the endometrium. Using either approach revealed a strong correlation with chronological age in the endometrium, providing solid evidence for age-related functional decline in this tissue. Furthermore, age acceleration/deceleration, as estimated by epigenetic clocks, might be a promising tool to predict or to gain insights into the origin of various endometrial pathologies, including recurrent implantation failure, cancer and endometriosis. Finally, there are several strategies to slow down or even reverse epigenetic clocks that might be applied to reduce the risk of age-related uterine impairments.The uterine factor should be considered, along with ovarian issues, to correct for the decline in female fertility with age. Epigenetic clocks can be tested to gain a deeper understanding of various endometrial disorders.© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.