STUDY QUESTION Is reproductive aging in granulosa cells associated with markers of ovarian reserve? SUMMARY ANSWER 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. WHAT IS KNOWN ALREADY 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. MAIN RESULTS AND THE ROLE OF CHANCE 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. WIDER IMPLICATIONS OF THE FINDINGS 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. TRIAL REGISTRATION NUMBER N/A.

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卵巢储备标志物与 IVF 患者颗粒细胞的生育年龄加速相关

研究问题 颗粒细胞的生殖衰老与卵巢储备标志物相关吗？摘要答案 年龄加速与抗苗勒氏管激素 (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胚胎的数量相关。已知信息 同龄女性的生殖衰老速度各不相同。DNA 甲基化可用于预测多种组织的表观遗传年龄。研究设计、规模、持续时间 这是一项针对 70 名女性在卵母细胞取出时进行的横断面研究。参与者/材料、环境、方法 本研究在一家学术医疗中心招募了 70 名参与者，他们在卵母细胞取出时提供了卵泡液样本。分离颗粒细胞并在 MmethylationEPIC 阵列上进行评估。线性回归用于评估颗粒细胞基于 DNA 甲基化的年龄预测与实际年龄之间的关联。年龄加速计算为基于 DNA 甲基化的回归年龄对实足年龄的残差。线性回归用于确定年龄加速与卵巢储备标志物和 IVF 周期结果之间的关联。主要结果和机会的作用 参与者的平均年龄为 36.7 ± 3.9 岁。就种族而言，54% 是白人，19% 是非裔美国人，27% 是其他背景。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，因此年龄加速较高的女性卵巢储备能力较低。年龄加速还与取出的卵母细胞总数（t = -3.9，P = 0.0002）、成熟卵母细胞数量（t = -3.8，P = 0.0003）以及受精卵母细胞或双原核卵母细胞的数量呈负相关。 (t = −2.8, P = 0.008) 在主要分析中。局限性和注意事项本研究使用了汇集的卵泡液，不允许对单个卵泡进行研究。不孕症患者也可能与一般人群不同，但是，由于我们使用颗粒细胞，参与者必须来自 IVF 人群。研究结果的更广泛意义这项研究表明，表观遗传年龄和年龄加速可以根据卵母细胞取出时收集的颗粒细胞计算出来。GrimAge 最有力地预测了实际年龄，而 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。研究经费/竞争利益 这项研究得到了美国国立卫生研究院 (UL1TR002378) 和 AKK 的女性健康跨学科研究职业计划 (K12HD085850) 的支持 内容完全由作者负责，并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发挥作用。JBS 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。JBS 已获得乔治亚州临床转化研究联盟的资助。HSH、JBS 和 AKS 已获得 NIH 的其他项目资助。AKK、SAG、SG、QSK、LJM 和 WS 没有利益冲突。试用注册号 不适用。