Epigenetic aging of mammalian gametes

Michael Klutstein, Nitzan Gonen

Research output: Contribution to journalReview articlepeer-review

2 Scopus citations


The process of aging refers to physiological changes that occur to an organism as time progresses and involves changes to DNA, proteins, metabolism, cells, and organs. Like the rest of the cells in the body, gametes age, and it is well established that there is a decline in reproductive capabilities in females and males with aging. One of the major pathways known to be involved in aging is epigenetic changes. The epigenome is the multitude of chemical modifications performed on DNA and chromatin that affect the ability of chromatin to be transcribed. In this review, we explore the effects of aging on female and male gametes with a focus on the epigenetic changes that occur in gametes throughout aging. Quality decline in oocytes occurs at a relatively early age. Epigenetic changes constitute an important part of oocyte aging. DNA methylation is reduced with age, along with reduced expression of DNA methyltransferases (DNMTs). Histone deacetylases (HDAC) expression is also reduced, and a loss of heterochromatin marks occurs with age. As a consequence of heterochromatin loss, retrotransposon expression is elevated, and aged oocytes suffer from DNA damage. In sperm, aging affects sperm number, motility and fecundity, and epigenetic changes may constitute a part of this process. 5 methyl-cytosine (5mC) methylation is elevated in sperm from aged men, but methylation on Long interspersed nuclear elements (LINE) elements is reduced. Di and trimethylation of histone 3 lysine 9 (H3K9me2/3) is reduced in sperm from aged men and trimethylation of histone 3 lysine 27 (H3K27me3) is elevated. The protamine makeup of sperm from aged men is also changed, with reduced protamine expression and a misbalanced ratio between protamine proteins protamine P1 and protamine P2. The study of epigenetic reproductive aging is recently gaining interest. The current status of the field suggests that many aspects of gamete epigenetic aging are still open for investigation. The clinical applications of these investigations have far-reaching consequences for fertility and sociological human behavior.

Original languageEnglish
Pages (from-to)785-803
Number of pages19
JournalMolecular Reproduction and Development
Issue number12
StatePublished - Dec 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Molecular Reproduction and Development published by Wiley Periodicals LLC.


This work was supported by the Israeli Science Foundation Grant 710/20 and the ERC StG project EnhanceSex (101039928) to N. G. and a BSF grant (2021180) to M. K. Views and opinions expressed are however those of the authors only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them.

FundersFunder number
European Research Council101039928
United States-Israel Binational Science Foundation2021180
Israel Science Foundation710/20


    • DNA methylation
    • aging
    • epigenetic modifications
    • gametes
    • oocytes
    • sperm


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