Aged Oocytes Research Articles

Dynamic mRNA degradome analyses indicate a role of histone H3K4 trimethylation in association with meiosis-coupled mRNA decay in oocyte aging

A decrease in oocyte developmental potential is a major obstacle for successful pregnancy in women of advanced age. However, the age-related epigenetic modifications associated with dynamic transcriptome changes, particularly meiotic maturation-coupled mRNA clearance, have not been adequately characterized in human oocytes. This study demonstrates a decreased storage of transcripts encoding key factors regulating the maternal mRNA degradome in fully grown oocytes of women of advanced age. A similar defect in meiotic maturation-triggered mRNA clearance is also detected in aged mouse oocytes. Mechanistically, the epigenetic and cytoplasmic aspects of oocyte maturation are synchronized in both the normal development and aging processes. The level of histone H3K4 trimethylation (H3K4me3) is high in fully grown mouse and human oocytes derived from young females but decreased during aging due to the decreased expression of epigenetic factors responsible for H3K4me3 accumulation. Oocyte-specific knockout of the gene encoding CxxC-finger protein 1 (CXXC1), a DNA-binding subunit of SETD1 methyltransferase, causes ooplasm changes associated with accelerated aging and impaired maternal mRNA translation and degradation. These results suggest that a network of CXXC1-maintained H3K4me3, in association with mRNA decay competence, sets a timer for oocyte deterioration and plays a role in oocyte aging in both mouse and human oocytes.

Atomic force spectroscopy-based essay to evaluate oocyte postovulatory aging.

Postovulatory aging is a process occurring in the mature (MII) oocyte leading the unfertilized ones to apoptosis. The optimal time window of fertility for different mammalian species after oocytes maturation depends on its timeliness: the higher the time elapsed from the accomplishment of the MII stage, the lower are the chances of fertilization and of development of a viable embryo. In the in vitro fertilization, the selection of competent oocytes for intracytoplasmic sperm injection (ICSI) is mostly made by the visual inspection of the MII oocyte morphology, which does not allow to determine the oocyte postovulatory age. On the other hand, more specific tests usually involve some kind of staining, thus compromising the viability of the oocyte for reproductive purposes. Hence, the need of a noninvasive analysis of oocyte aging to improve the success rate of in vitro fertilization procedures. Here, we exploit atomic force microscopy to examine the evolution of the mechanical properties of mouse oocytes during in vitro postovulatory aging. Three hours before the occurrence of any visual morphological feature related to degradation, we observe a sudden change of the mechanical parameters: the elastic modulus doubles its initial value, while the viscosity decreases significantly. These mechanical variations are temporally correlated with the release of the cortical granules, investigated by fluorescence microscopy. Interestingly, the oocyte mechanics correlates as well with the yield of embryo formation, evaluated up to the blastocyst formation stage. These results demonstrate that minimally invasive mechanical measurements are very sensitive to the aging of the oocyte and can be used as a label‐free method to detect the age of the postovulatory oocytes.

Pleiotropic Effects of IGF1 on the Oocyte.

A woman’s endocrine system plays a crucial role in orchestrating cellular interactions throughout her life. The growth hormone (GH) and insulin-like growth factor (IGF) system appears to impact crucial reproductive events and cell types of the ovary, such as granulosa cells, theca cells, and oocytes. Further, IGF1 is a cornerstone during embryonic development and influences predominantly developing and pre-antral follicles. In this commentary, we will emphasize the pleiotropic effects of IGF1 on physiological processes inside the egg. Herein, we will provide a brief overview on IGF1 related cell signal transduction pathways during the maturation and aging of oocytes. We aim to elucidate from a molecular and biochemical point of view if IGF1 in women with metabolic imbalances such as obesity or diabetes could be used in clinics as a novel, reliable estimator for the developmental competence of an oocyte.

3,3'-Diindolylmethane Supplementation Maintains Oocyte Quality by Reducing Oxidative Stress and CEP-1/p53-Mediated Regulation of Germ Cells in a Reproductively Aged Caenorhabditis elegans Model.

In recent decades, maternal age at first birth has increased, as has the risk of infertility due to rapidly declining oocyte quality with age. Therefore, an understanding of female reproductive aging and the development of potential modulators to control oocyte quality are required. In this study, we investigated the effects of 3,3′-diindolylmethane (DIM), a natural metabolite of indole-3-cabinol found in cruciferous vegetables, on fertility in a Caenorhabditis elegans model. C. elegans fed DIM showed decreased mitochondrial dysfunction, oxidative stress, and chromosomal aberrations in aged oocytes, and thus reduced embryonic lethality, suggesting that DIM, a dietary natural antioxidant, improves oocyte quality. Furthermore, DIM supplementation maintained germ cell apoptosis (GCA) and germ cell proliferation (GCP) in a CEP-1/p53-dependent manner in a reproductively aged C. elegans germ line. DIM-induced GCA was mediated by the CEP-1-EGL-1 pathway without HUS-1 activation, suggesting that DIM-induced GCA is different from DNA damage-induced GCA in the C. elegans germ line. Taken together, we propose that DIM supplementation delays the onset of reproductive aging by maintaining the levels of GCP and GCA and oocyte quality in a reproductively aged C. elegans.

RETRACTED: Parallel bimodal single-cell sequencing of transcriptome and methylome provides molecular and translational insights on oocyte maturation and maternal aging

Advanced maternal aging has become a worldwide public health issue contributing to female fertility decline. To provide a complete landscape of transcriptome and epigenetic changes during oocyte aging and maturation, we applied a parallel bimodal genomics approach to parallel transcriptome and methylome profiles of mouse oocytes at single-cell and single-base resolution. Age-associated gene expression changes were associated with defective spindle assembly and mitochondrial dysfunction. Parallel sequencing data suggested aged-related defects in mRNA degradation and methylome remodelling during oocyte maturation. Differentially methylated region in aged mature oocyte was associated with trimethylation of Histone H3 at Lysine 4. More importantly, RNA expression-based prediction model for assessing maturation and oocytes age. Taken together, our work provides a better understanding of molecular mechanisms during mouse oocyte aging, points a new direction of oocyte quality assessment and paves the way for developing novel treatments to improve oocyte quality.

How slow is too slow? A comprehensive portrait of Day 7 blastocysts and their clinical value standardized through artificial intelligence.

How slow is too slow? A comprehensive portrait of Day 7 blastocysts and their clinical value standardized through artificial intelligence.

Comparison of three antioxidants in chemical and biological assays on porcine oocytes during ageing in vitro.

Our previous studies have already revealed that β-cryptoxanthin (BCX), hesperetin (HES), and icariin (ICA) antioxidants are effective for in vitro maturation (IVM) of porcine oocytes. In this study, we investigated which of BCX, HES, or ICA was more effective for IVM of porcine oocytes. The antioxidant properties were assessed with aged porcine oocytes and embryos by comparing 2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl (DPPH), reducing power, and H2O2 scavenging activity assays. The chemical assay results demonstrated that BCX had a greater DPPH scavenging activity and reducing power than HES and ICA, compared with controls. However, the H2O2 scavenging activity of the antioxidants was similar when tested at the optimal concentrations of 1 μM BCX (BCX-1), 100 μM HES (HES-100), and 5 μM ICA (ICA-5). The biological assay results showed that BCX-1 treatment was more effective in inducing a significant reduction in reactive oxygen species (ROS), improving glutathione levels, and increasing the expression of antioxidant genes. In addition, BCX-1 inhibited apoptosis by increasing the expression of anti-apoptotic genes and decreasing pro-apoptotic genes in porcine parthenogenetic blastocysts. BCX-1 also significantly increased the blastocyst formation rate compared with the ageing control group, HES-100 and ICA-5. This study demonstrates that damage from ROS produced during oocyte ageing can be prevented by supplementing antioxidants into the IVM medium, and BCX may be a potential candidate to improve assisted reproductive technologies.

Aberrant Expression of Mitochondrial SAM Transporter SLC25A26 Impairs Oocyte Maturation and Early Development in Mice.

The immature germinal vesicle (GV) oocytes proceed through metaphase I (MI) division, extrude the first polar body, and become mature metaphase II (MII) oocytes for fertilization which is followed by preimplantation and postimplantation development until birth. Slc25a26 is the gene encoding S-adenosylmethionine carrier (SAMC), a member of the mitochondrial carrier family. Its major function is to catalyze the uptake of S-adenosylmethionine (SAM) from cytosol into mitochondria, which is the only known mitochondrial SAM transporter. In the present study, we demonstrated that excessive SLC25A26 accumulation in mouse oocytes mimicked naturally aged oocytes and resulted in lower oocyte quality with decreased maturation rate and increased reactive oxygen species (ROS) by impairing mitochondrial function. Increased level of Slc25a26 gene impacted gene expression in mouse oocytes such as mt-Cytb which regulates mitochondrial respiratory chain. Furthermore, increased level of Slc25a26 gene in fertilized oocytes slightly compromised blastocyst formation, and Slc25a26 knockout mice displayed embryonic lethality around 10.5 dpc. Taken together, our results showed that Slc25a26 gene plays a critical role in oocyte maturation and early mouse development.

Epitalon protects against post-ovulatory aging-related damage of mouse oocytes in vitro.

The developmental potential of oocytes decreases with time after ovulation in vivo or in vitro. Epitalon is a synthetic short peptide made of four amino acids (alanine, glutamic acid, aspartic acid, and glycine), based on a natural peptide called epithalamion extracted from the pineal gland. It is a potent antioxidant, comparable to melatonin, that may confer longevity benefits. The current study aims to test the protective effects of Epitalon on the quality of post-ovulatory aging oocytes. Epitalon at 0.1mM was added to the culture medium, and the quality of oocytes was evaluated at 6h, 12h, and 24h of culture. We found that 0.1mM Epitalon reduced intracellular reactive oxygen species. Epitalon treatment significantly decreased frequency of spindle defects and abnormal distribution of cortical granules during aging for 12h and 24h, while increased mitochondrial membrane potential and DNA copy number of mitochondria, thus decreasing apoptosis of oocytes by 24h of in vitro aging. Our results suggest that Epitalon can delay the aging process of oocytes in vitro via modulating mitochondrial activity and ROS levels.

Procyanidin B2 Protects Aged Oocytes Against Meiotic Defects Through Cortical Tension Modulation.

Defects in meiotic process are the main factors responsible for the decreased developmental competence in aged oocytes. Our recent research indicated that natural antioxidant procyanidin B2 (PCB2) promoted maturation progress in oocytes from diabetic mice. However, the effect of PCB2 on aging-induced chromosome abnormalities and the underlying mechanism have not been explored. Here, we found that PCB2 recovered aging-caused developmental arrest during meiotic maturation, germinal vesicle breakdown (GVBD) rate was significantly higher in aged oocytes treated with PCB2 (P < 0.05). Furthermore, we discovered that cortical mechanics were altered during aging process, cortical tension-related proteins were aberrantly expressed in aged oocytes (P < 0.001). PCB2 supplementation efficaciously antagonized aging-induced decreased cortical tension (P < 0.001). Moreover, PCB2 restored spindle morphology (P < 0.01), maintained proper chromosome alignment (P < 0.05), and dramatically reduced reactive oxygen species (ROS) level (P < 0.05) in aged oocytes. Collectively, our results reveal that PCB2 supplementation is a feasible approach to protect oocytes from reproductive aging, contributing to the improvement of oocytes quality.

Reproductive Outcome After GnRH Agonist Triggering With Co-Administration of 1500 IU hCG on the Day of Oocyte Retrieval in High Responders: A Long-Term Retrospective Cohort Study

While triggering oocyte maturation with GnRH agonist (GnRHa) seems to be safe and effective in terms of the risk of developing OHSS and the number of metaphase II oocytes, it nevertheless results in luteal phase deficiency. To date, strategies have been developed in order to rescue defective luteal phase of GnRHa triggered cycles. Our study aimed to assess the reproductive outcome of GnRHa triggered cycles combined with modified luteal support (1500 IU hCG at the day of oocyte retrieval) in women with high ovarian response and to compare the outcome with hCG triggered cycles in GnRH antagonist IVF-ICSI procedures. A retrospective cohort database review of the results of GnRH antagonist IVF-ICSI cycles was conducted at a tertiary-care IVF center in Ljubljana, Slovenia. A total of 6126 cycles, performed from January 1, 2014, to December 31, 2020, were included in the final analysis. Final oocyte maturation was performed with either 5000, 6500, or 10,000 IU hCG (women with normal ovarian response) or 0.6 mg GnRHa (buserelin), supplemented with 1500 IU hCG on the day of oocyte retrieval (in women with high ovarian response). In cases of excessive ovarian response and/or high risk of OHSS luteal support was not introduced and all good quality blastocysts were frozen. According to significant differences in patients’ age and the number of oocytes in the two groups, matching by age and number of oocytes was performed. No significant differences were observed regarding pregnancy rate per embryo transfer, rate of early pregnancy loss, and livebirth rate per pregnancy between the GnRHa and hCG trigger groups, respectively. A significant difference in the number of developed embryos and blastocysts, as well as the number of frozen blastocysts, was seen in favor of the GnRHa trigger. However, the birth weight in the GnRHa trigger group was significantly lower.ConclusionThe results of our study support the use of GnRHa for final oocyte maturation in GnRH antagonist IVF cycles in women with high ovarian response. Luteal phase rescue was performed by co-administration of 1500 IU hCG on the day of oocyte retrieval and estradiol and progesterone supplementation. In our experience, such an approach results in a comparable reproductive outcome with hCG trigger group.

Genetic counseling decisions in gestational carrier pregnancies.

Pregnancies conceived as contracted gestational carriers are a relatively new phenomenon for reproductive medicine. Since the intended parents control genetic screening decisions, there may be differences in genetic decisions made for gestational carrier (GC) in vitro fertilization (IVF) pregnancies as compared to traditional non-gestational carrier IVF pregnancies. Our goal was to investigate the frequency and types of these genetic testing decisions. We performed a retrospective study of GC pregnancies counseled at a private maternal-fetal medicine practice between January 2006 and January 2021. Inclusion criteria were pregnancies thatcompleted counseling with a certified genetic counselor and obtained high-resolution imaging. Controls were non-GC IVF pregnancies seen in the same period matched by parity, estimated delivery date (EDD), and the oocyte age utilized in conception. Statistical analysis included patient demographics, pre-implantation genetic testing (PGT-A) frequency and results, ultrasound imaging results, and the frequency with results of prenatal genetic screening (first or second-trimester serum screens), non-invasive prenatal testing (NIPT), or diagnostic testing (chorionic venous sampling (CVS) or amniocentesis). One hundred and ninety onegestational carrier pregnancies were identified and 167 met inclusion criteria. Gestational carrier pregnancies were significantly more likely to pursue PGT-A, PGT-A with NIPT, first-trimester screening, and second-trimester screening. There were no differences in rates of amniocentesis or CVS over controls. Regarding genetic counseling and screening options, our series is the first to demonstrate that gestational carrier parents seek additional genetic counseling resources, even with reassuring PGT-A and ultrasound.

Cytogenetic abnormalities in a sample of females with premature ovarian failure

BackgroundPremature ovarian failure (POF) is a complex heterogeneous disorder characterized by the triad of amenorrhea, hypergonadotropinism, and hypoestrogenism in women before the expected age of menopause. In most POF patients, the etiology is idiopathic. X chromosome abnormalities are known to be responsible for many POF cases but the effect of sex chromosome low level mosaicism on ovarian function still remains unclear. The aim of this study was to investigate the prevalence and type of cytogenetic abnormalities as well as low-level sex chromosome mosaicism in Egyptian females with POF.ResultsThe present study recruited thirty women with POF and thirty women with normal reproductive history as a control group. Conventional cytogenetic analysis was carried out on POF patients in order to detect cytogenetic abnormalities. FISH on interphase and metaphase nuclei from patients with normal karyotype as well as from thirty control women with normal reproductive history was performed using X, Y, and 18 centromeric probes to evaluate low-level sex chromosome mosaicism. Conventional cytogenetic analysis of peripheral blood lymphocytes demonstrated chromosomal aberrations in 7 cases. FISH revealed that the rate of X chromosome mosaicism was significantly higher in POF patients than in the control group.ConclusionWe concluded that X chromosome abnormalities including low level mosaicism may be underlying the pathology of POF as increased mosaicism may lead to accelerated oocyte aging and premature follicular atresia.

CDC26 Is a Key Factor in Human Oocyte Aging

(Abstracted from Hum Reprod 2021;36:3095–3107) Declining oocyte fertilization capacity and developmental potential, involving deficits in both nucleus and cytoplasm contributing to aberrant meiosis, is the major contributor to declining fertility and increased rate of congenital birth defects in women older than the age of 35 years. Oocyte aging is directly affected by a variety of factors, both environmental and intrinsic; however, the precise mechanism remains unclear.

The Spontaneous Nitric Oxide Production during Mouse Oocyte Maturation and Aging Process

The Spontaneous Nitric Oxide Production during Mouse Oocyte Maturation and Aging Process

Multispectral autofluorescence characteristics of reproductive aging in old and young mouse oocytes

Increasing age has a major detrimental impact on female fertility, which, with an ageing population, has major sociological implications. This impact is primarily mediated through deteriorating quality of the oocyte. Deteriorating oocyte quality with biological age is the greatest rate-limiting factor to female fertility. Here we have used label-free, non-invasive multi-spectral imaging to identify unique autofluorescence profiles of oocytes from young and aged animals. Discriminant analysis demonstrated that young oocytes have a distinct autofluorescent profile which accurately distinguishes them from aged oocytes. We recently showed that treatment with the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) restored oocyte quality and fertility in aged animals, and when our analysis was applied to oocytes from aged animals treated with NMN, 85% of these oocytes were classified as having the autofluorescent signature of young animals. Spectral unmixing using the Robust Dependent Component Analysis (RoDECA) algorithm demonstrated that NMN treatment altered the metabolic profile of oocytes, increasing free NAD(P)H, protein bound NAD(P)H, redox ratio and the ratio of bound to free NAD(P)H. The frequency of oocytes with simultaneously high NAD(P)H and flavin content was also significantly increased in mice treated with NMN. Young and Aged + NMN oocytes had a smoother spectral distribution, with the distribution of NAD(P)H in young oocytes specifically differing from that of aged oocytes. Identifying the multispectral profile of oocyte autofluorescence during aging could have utility as a non-invasive and sensitive measure of oocyte quality.

Loss of heterochromatin and retrotransposon silencing as determinants in oocyte aging.

Mammalian oocyte quality reduces with age. We show that prior to the occurrence of significant aneuploidy (9M in mouse), heterochromatin histone marks are lost, and oocyte maturation is impaired. This loss occurs in both constitutive and facultative heterochromatin marks but not in euchromatic active marks. We show that heterochromatin loss with age also occurs in human prophase I‐arrested oocytes. Moreover, heterochromatin loss is accompanied in mouse oocytes by an increase in RNA processing and associated with an elevation in L1 and IAP retrotransposon expression and in DNA damage and DNA repair proteins nuclear localization. Artificial inhibition of the heterochromatin machinery in young oocytes causes an elevation in retrotransposon expression and oocyte maturation defects. Inhibiting retrotransposon reverse‐transcriptase through azidothymidine (AZT) treatment in older oocytes partially rescues their maturation defects and activity of the DNA repair machinery. Moreover, activating the heterochromatin machinery via treatment with the SIRT1 activating molecule SRT‐1720, or overexpression of Sirt1 or Ezh2 via plasmid electroporation into older oocytes causes an upregulation in constitutive heterochromatin, downregulation of retrotransposon expression, and elevated maturation rates. Collectively, our work demonstrates a significant process in oocyte aging, characterized by the loss of heterochromatin‐associated chromatin marks and activation of specific retrotransposons, which cause DNA damage and impair oocyte maturation.

Abstract P4-10-16: Increased chemotherapy-induced ovarian reserve loss and impaired oocyte quality in a mouse ATM knock-down model: An augury for women with ATM-pathway-pathogenic-variants-associated breast cancer?

Abstract Rationale: Breast cancer chemotherapy commonly causes the depletion of ovarian primordial follicle reserve, which results in premature ovarian insufficiency and infertility. It is critical to understand the mechanism of this ovarian damage to be able to develop pharmacological fertility preservation methods. We have previously shown that the main mechanism of ovarian follicle loss induced by cyclophosphamide (C) and doxorubicin (A) is via the induction of double-strand DNA breaks (DSBs) and the resulting apoptotic death of primordial follicles. We have also shown that some oocytes may repair this damage by activating the ATM-mediated DNA DSB repair pathway (ATM-Pathway). We have also demonstrated that the oocytes of women with BRCA1 pathogenic variants are more prone to DNA damage and such women are more likely to lose ovarian reserve after AC-based chemotherapy. BRCA1 is a key member of the ATM-Pathway. An increasing number of women are diagnosed with breast cancer associated with mutations of the other members of the ATM-Pathway. This includes ATM, which is the orchestrator of the ATM-Pathway. Therefore, we hypothesized that ATM-deficient oocytes may be more prone to chemotherapy-induced damage. In addition, given our recent findings of the role of declining BRCA1 function in oocyte aging, we hypothesized that ATM function is important in oocyte and embryo quality. Having both increased liability to chemotherapy-induced loss and accelerated ovarian aging can be a double-whammy for women with breast cancer that are associated with the pathogenic variants of the ATM-Pathway genes. Methods: Germinal Vesicle (GV) stage oocytes were collected from 6-wk old mice 48h after ovarian stimulation. Oocytes were then microinjected with 50uM ATM small interfering RNA (siRNA). The scrambled-siRNA-injected and un-injected oocytes served as negative controls. In separate experiments, effective ATM-knockdown (~70%) was confirmed by single-cell real-time-qPCR. Then, oocytes were subjected to subsequent in vitro maturation followed by parthenogenesis or 4h exposure to the active metabolite of cyclophosphamide, 4-hydroperoxycyclophosphamide (4-HC, 20µg/mL). Experiments were repeated ≥ thrice. One-way ANOVA and non-parametric Kruskal-Wallis posthoc tests were used for statistical analysis.Results: ATM-knockdown resulted in a significant reduction of oocyte maturation compared with scrambled or uninjected (29%, n=157 vs. 78%, n=172 vs. 84%, n=151) (p&amp;lt;0.001 siATM vs. the controls), suggesting altered oocyte quality. The siATM parthenotes had lower cleavage and blastocyst rates (15% and 0%, n=20,) compared with scrambled (63% and 18%, n=22), and uninjected controls (66% and 24%, n=21) (p&amp;lt;0.05 compared to either control), and demonstrated impaired morphology. Moreover, ATM-knock-down resulted in increased oocyte sensitivity to chemotherapy; with significantly lower survival rates (15%, n=37) compared to scrambled (55%, n=48) or un-injected controls (57% n=48; p&amp;lt;0.001) after the 4-HC exposure. Conclusions: This mouse model indicates that intact ATM function is critical in both oocyte resistance against chemotherapy and the maintenance of egg and embryo quality. Clinical studies are justified to determine if women with ATM pathogenic variants have impaired egg and embryo quality and are more prone to chemotherapy-induced loss of ovarian reserve and fertility. Citation Format: Kutluk H Oktay, Xiu Tan, Katarzyna Szymanska-Vandendriessche. Increased chemotherapy-induced ovarian reserve loss and impaired oocyte quality in a mouse ATM knock-down model: An augury for women with ATM-pathway-pathogenic-variants-associated breast cancer? [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-16.

Systematic Understanding of Anti-Aging Effect of Coenzyme Q10 on Oocyte Through a Network Pharmacology Approach.

BackgroundMaternal oocyte aging is strongly contributing to age-related decline in female fertility. Coenzyme Q10 (CoQ10) exerts positive effects in improving aging-related deterioration of oocyte quality, but the exact mechanism is unclear.ObjectiveTo reveal the system-level mechanism of CoQ10’s anti-aging effect on oocytes based on network pharmacology.MethodsThis study adopted a systems network pharmacology approach, including target identification, data integration, network and module construction, bioinformatics analysis, molecular docking, and molecular dynamics simulation.ResultA total of 27 potential therapeutic targets were screened out. Seven hub targets (PPARA, CAT, MAPK14, SQSTM1, HMOX1, GRB2, and GSR) were identified. Functional and pathway enrichment analysis indicated that these 27 putative targets exerted therapeutic effects on oocyte aging by regulating signaling pathways (e.g., PPAR, TNF, apoptosis, necroptosisn, prolactin, and MAPK signaling pathway), and are involved oxidation-reduction process, mitochondrion, enzyme binding, reactive oxygen species metabolic process, ATP binding, among others. In addition, five densely linked functional modules revealed the potential mechanisms of CoQ10 in improving aging-related deterioration of oocyte quality are closely related to antioxidant, mitochondrial function enhancement, autophagy, anti-apoptosis, and immune and endocrine system regulation. The molecular docking study reveals that seven hub targets have a good binding affinity towards CoQ10, and molecular dynamics simulation confirms the stability of the interaction between the hub targets and the CoQ10 ligand.ConclusionThis network pharmacology study revealed the multiple mechanisms involved in the anti-aging effect of CoQ10 on oocytes. The molecular docking and molecular dynamics simulation provide evidence that CoQ10 may act on these hub targets to fight against oocytes aging.

FAM111A Is a Novel Molecular Marker for Oocyte Aging.

Aging is the main cause of decline in oocyte quality, which can further trigger the failure of assisted reproductive technology (ART). Exploring age-related genes in oocytes is an important way to investigate the molecular mechanisms involved in oocyte aging. To provide novel insight into this field, we performed a pooled analysis of publicly available datasets, using the overlapping results of two statistical methods on two Gene Expression Omnibus (GEO) datasets. The methods utilized in the current study mainly include Spearman rank correlation, the Wilcoxon signed-rank test, t-tests, Venn diagrams, Gene Ontology (GO), Protein–Protein Interaction (PPI), Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and receiver operating characteristic (ROC) curve analysis. We identified hundreds of age-related genes across different gene expression datasets of in vitro maturation-metaphase II (IVM-MII) oocytes. Age-related genes in IVM-MII oocytes were involved in the biological processes of cellular metabolism, DNA replication, and histone modifications. Among these age-related genes, FAM111A expression presented a robust correlation with age, seen in the results of different statistical methods and different datasets. FAM111A is associated with the processes of chromosome segregation and cell cycle regulation. Thus, this enzyme is potentially an interesting novel marker for the aging of oocytes, and warrants further mechanistic study.