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Review
. 2024 Feb 1;15(1):5-21.
doi: 10.14336/AD.2023.0527.

Oocyte Aging: A Multifactorial Phenomenon in A Unique Cell

Pawel Kordowitzki  1 , Szymon Graczyk  1 , Amin Haghani  2   3 , Michael Klutstein  4
Affiliations
Review

Oocyte Aging: A Multifactorial Phenomenon in A Unique Cell

Pawel Kordowitzki et al. Aging Dis. .

Abstract

The oocyte is considered to be the largest cell in mammalian species. Women hoping to become pregnant face a ticking biological clock. This is becoming increasingly challenging as an increase in life expectancy is accompanied by the tendency to conceive at older ages. With advancing maternal age, the fertilized egg will exhibit lower quality and developmental competence, which contributes to increased chances of miscarriage due to several causes such as aneuploidy, oxidative stress, epigenetics, or metabolic disorders. In particular, heterochromatin in oocytes and with it, the DNA methylation landscape undergoes changes. Further, obesity is a well-known and ever-increasing global problem as it is associated with several metabolic disorders. More importantly, both obesity and aging negatively affect female reproduction. However, among women, there is immense variability in age-related decline of oocytes' quantity, developmental competence, or quality. Herein, the relevance of obesity and DNA-methylation will be discussed as these aspects have a tremendous effect on female fertility, and it is a topic of continuous and widespread interest that has yet to be fully addressed for the mammalian oocyte.

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Conflict of interest statement

Conflict of interest

The Authors declare no Competing Financial or Non-Financial Interests.

Figures

Figure 1.
Figure 1.
DNA methylation in human eggs with regards to aging. (A) Scheme showing the mechanism of methylation and demethylation of cytosine. (B) Scheme showing the consequences of advanced maternal age (especially in women at the age of 35 years and above) and how an accelerated and a deaccelerated aging process could impact the DNA-methylation age of oocytes. The oocytes in ovarian follicles are arrested in Prophase of the first meiotic division, and with advancing maternal age, more errors are likely after the resumption of meiosis what could lead to aneuploidies in the offspring (e.g., Trisomy 21/Down-Syndrome). Abbreviations: AMH=Anti-Muellerian Hormone, DNMT= DNA methyltransferase, TDG= Thymine DNA glycosylase, TET= ten-eleven translocation.
Figure 2.
Figure 2.
Scheme showing potential outcomes in case of maternal obesity and Stella insufficiency.
Figure 3.
Figure 3.
Scheme showing the working mechanism of the so-called writers and erasers. Writers are the MTTL3-14 complex, and the so- called erasers, are FTO and ALKBH5, which are necessary for the transfer of methyl groups between adenosine (A)and N6-methyladenosine (m6A).
Figure 4.
Figure 4.
Scheme showing the three pathways of unfolded protein response (UPR) during ER stress. The branches of the UPR are characterized by: (left branch) ATF6 passes from the lumen of the ER into the cytosol in the Golgi apparatus, where it is cleaved by site 1 protease (S1P) and site protease 2 (S2P). The cytosolically active fragment of ATF6 migrates to the cell nucleus and activates transcription of UPR target genes involved in ER protein folding homeostasis; (middle branch) PERK phosphorylates the α-subunit of eukaryotic translation initiation factor 2 (eIF2α). Some selective mRNAs, for example, ATF4 mRNA, are preferentially translated when eIF2α is phosphorylated; (right branch) RNase IRE1α is able to cleave ER-bound mRNA or miRNA upon degradation via IRE1-dependent regulated cleavage (RIDD), affecting protein folding charge, cellular metabolism, and inflammatory signaling pathways. The cytosolic domain ofIRE1α may also provide a scaffold for the recruitment of adapter proteins, such as members of the tumor necrosis factor receptor-associated factor (TRAF) family. In addition, IRE1α RNase combines mRNA from XBP1, which encodes a potent transcription factor that activates the expression of UPR target genes involved in ER proteostasis and cellular pathophysiology. Notably, unfolded or misfolded proteins that accumulate in the lumen of the ER can be degraded by proteasome-based ER-associated protein degradation (ERAD).
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Grants and funding

We want to thank Norbert Gleicher and David Albertini for their critical comments during the writing of this article. Figures have been created with biorender.com, access date 03.09.2022. This work was supported by the IDUB Debiuty grant [Nr. 4101.00000066].

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