Division of Research, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, USA.
Division of Reproductive Endocrinology and Infertility, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, USA.
Hum Reprod. 2022 Sep 30;37(10):2438-2445. doi: 10.1093/humrep/deac178.
Is reproductive aging in granulosa cells associated with markers of ovarian reserve?
Age acceleration was associated with anti-Mullerian hormone (AMH) levels, antral follicle count (AFC), oocyte yield and maturity, and the number of successfully fertilized embryos.
The rate of reproductive aging varies among women of the same age. DNA methylation can be used to predict epigenetic age in a variety of tissues.
STUDY DESIGN, SIZE, DURATION: This was a cross-sectional study of 70 women at the time of oocyte retrieval.
PARTICIPANTS/MATERIALS, SETTING, METHODS: The 70 participants were recruited for this study at an academic medical center and they provided follicular fluid samples at the time of oocyte retrieval. Granulosa cells were isolated and assessed on the MethylationEPIC array. Linear regression was used to evaluate the associations between DNA methylation-based age predictions from granulosa cells and chronological age. Age acceleration was calculated as the residual of regressing DNA methylation-based age on chronological age. Linear regressions were used to determine the associations between age acceleration and markers of ovarian reserve and IVF cycle outcomes.
Participants were a mean of 36.7 ± 3.9 years old. In regards to race, 54% were white, 19% were African American and 27% were of another background. Age acceleration was normally distributed and not associated with chronological age. Age acceleration was negatively associated with AMH levels (t = -3.1, P = 0.003) and AFC (t = -4.0, P = 0.0001), such that women with a higher age acceleration had a lower ovarian reserve. Age acceleration was also negatively correlated with the total number of oocytes retrieved (t = -3.9, P = 0.0002), the number of mature oocytes (t = -3.8, P = 0.0003) and the number of fertilized oocytes or two-pronuclear oocytes (t = -2.8, P = 0.008) in the main analysis.
LIMITATIONS, REASONS FOR CAUTION: This study used pooled follicular fluid, which does not allow for the investigation of individual follicles. Infertility patients may also be different from the general population, but, as we used granulosa cells, the participants had to be from an IVF population.
This study demonstrated that epigenetic age and age acceleration can be calculated from granulosa cells collected at the time of oocyte retrieval. GrimAge most strongly predicted chronological age, and GrimAge acceleration was associated with baseline and cycle characteristics as well as cycle outcomes, which indicates its potential clinical relevance in evaluating both oocyte quantity and quality.
STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Institutes of Health (UL1TR002378) and the Building Interdisciplinary Research Careers in Women's Health Program (K12HD085850) to A.K.K. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding source had no role in any aspect of this study. J.B.S. serves as Vice Chair for the American Society for Reproductive Medicine Education Committee, is a Medical Committee Advisor for the Jewish Fertility Foundation and works with Jscreen. J.B.S. has received funding from Georgia Clinical Translational Research Alliance. H.S.H., J.B.S. and A.K.S. have received NIH funding for other projects. A.K.K., S.A.G., S.G., Q.S.K., L.J.M. and W.S. have no conflicts of interest.
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颗粒细胞的生殖衰老是否与卵巢储备标志物相关？
年龄加速与抗苗勒管激素（AMH）水平、窦卵泡计数（AFC）、卵母细胞产量和成熟度以及成功受精的胚胎数量相关。
女性的生殖衰老速度在同年龄段的女性中存在差异。DNA 甲基化可用于预测多种组织中的表观遗传年龄。
研究设计、大小、持续时间：这是一项在卵母细胞采集时对 70 名女性进行的横断面研究。
参与者/材料、设置、方法：70 名参与者在学术医疗中心被招募参与本研究，并在卵母细胞采集时提供卵泡液样本。分离出颗粒细胞并在 MethylationEPIC 阵列上进行评估。线性回归用于评估从颗粒细胞得出的基于 DNA 甲基化的年龄预测与实际年龄之间的相关性。年龄加速通过将 DNA 甲基化年龄回归到实际年龄的残差来计算。线性回归用于确定年龄加速与卵巢储备和 IVF 周期结果之间的相关性。
参与者的平均年龄为 36.7±3.9 岁。在种族方面，54%为白人，19%为非裔美国人，27%为其他背景。年龄加速呈正态分布，与实际年龄无关。年龄加速与 AMH 水平（t=-3.1，P=0.003）和 AFC（t=-4.0，P=0.0001）呈负相关，即年龄加速越高的女性卵巢储备越低。年龄加速与采集的卵母细胞总数（t=-3.9，P=0.0002）、成熟卵母细胞数量（t=-3.8，P=0.0003）和受精卵母细胞或双原核卵母细胞数量（t=-2.8，P=0.008）呈负相关。
局限性、谨慎原因：本研究使用了 pooled follicular fluid，无法对单个卵泡进行研究。不孕患者也可能与一般人群不同，但由于我们使用了颗粒细胞，参与者必须来自 IVF 人群。
本研究表明，可从卵母细胞采集时收集的颗粒细胞中计算出表观遗传年龄和年龄加速。GrimAge 最能预测实际年龄，并且 GrimAge 加速与基线和周期特征以及周期结果相关，这表明其在评估卵母细胞数量和质量方面具有潜在的临床相关性。
研究资金/竞争利益：本研究由美国国立卫生研究院（UL1TR002378）和妇女健康跨学科研究职业发展计划（K12HD085850）资助，A.K.K. 是唯一的作者，对研究内容的真实性和解释负责，内容仅代表作者的观点，不一定代表美国国立卫生研究院的官方观点。资金来源在本研究的任何方面都没有任何作用。J.B.S. 担任美国生殖医学学会教育委员会副主席、犹太生育基金会医学委员会顾问，并与 Jscreen 合作。J.B.S. 获得了格鲁吉亚临床转化研究联盟的资助。H.S.H.、J.B.S. 和 A.K.K. 获得了 NIH 资助的其他项目。A.K.K.、S.A.G.、S.G.、Q.S.K.、L.J.M. 和 W.S. 没有利益冲突。
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