Review

*Author for correspondence:

Research Division, Department of Gynecology & Obstetrics, Emory University School of Medicine, Atlanta, GA 30322, USA

Reproductive Endocrinology & Infertility Division, Department of Gynecology & Obstetrics, Emory University School of Medicine, Atlanta, GA 30322, USA

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Alicia K Smith

https://orcid.org/0000-0002-8537-5156

Research Division, Department of Gynecology & Obstetrics, Emory University School of Medicine, Atlanta, GA 30322, USA

Reproductive Endocrinology & Infertility Division, Department of Gynecology & Obstetrics, Emory University School of Medicine, Atlanta, GA 30322, USA

Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA

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Published Online:22 Dec 2023https://doi.org/10.2217/epi-2023-0298

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Abstract

People with ovaries experience reproductive aging as their reproductive function and system declines. This has significant implications for both fertility and long-term health, with people experiencing an increased risk of cardiometabolic disorders after menopause. Reproductive aging can be assessed through markers of ovarian reserve, response to fertility treatment or molecular biomarkers, including DNA methylation. Changes in DNA methylation with age associate with poorer reproductive outcomes, and epigenome-wide studies can provide insight into genes and pathways involved. DNA methylation-based epigenetic clocks can quantify biological age in reproductive tissues and systemically. This review provides an overview of hallmarks and theories of aging in the context of the reproductive system, and then focuses on studies of DNA methylation in reproductive tissues.

Plain language summary

People with ovaries experience a natural decline in the function of their reproductive system as they age. This decline eventually leads to menopause, and after menopause, people have an increased risk of developing cardiovascular or other chronic diseases. In the clinic, it is hard to measure aging of the reproductive system, so other markers of the ovary's function, like the number of remaining eggs, are used. We can also measure reproductive aging using molecular biomarkers, which can help us determine when a person's molecular age is different from their chronological age. This review focuses on an overview of biological processes and theories associated with aging, and then focuses on what can be learned from molecular biomarkers.

Tweetable abstract

Biological and chronological aging of the reproductive system can occur at different rates and through different mechanisms. We can quantify consequences of reproductive aging on individual CpG sites or by using epigenetic clocks.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

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Received 24 August 2023

Accepted 5 December 2023

Published online 22 December 2023

Published in print February 2024

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Author contributions

All authors made substantial contributions to the conception or design of the work, drafted or critical revised the work, gave final approval of the version to be published and agree to be accountable for all aspects of the work.

Financial disclosure

Supported by the Robert W Woodruff Health Science Center and the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR002378. Additional support from R21HD110847 and K01AG078497. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. We will comply with NIH policy to submit an electronic version of the final peer-reviewed manuscript to the National Library of Medicine's PubMed Central.

Competing interests disclosure

JB Spencer serves on the medical advisory council for the Jewish Fertility Foundation. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

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The content is solely the responsibility of the authors and does not necessarily represent the official views of the Robert W Woodruff Health Science Center or the National Institutes of Health.

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DNA methylation as a window into female reproductive aging

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