表观遗传学时钟利用CpG DNA甲基化（DNAm）来估计生物年龄；加速与癌症、心脏病和寿命缩短相关。很少有研究评估DNAm年龄和妊娠结果。AgeAccelGrim是一个结合了七个DNAm组分的新型表观遗传时钟。本研究旨在确定母亲生物老化（通过AgeAccelGrim）是否与早发性早产相关。纳入了在三甲大学医院分娩的单胎高风险自发性早产（PTB）患者的前瞻性队列研究。使用Illumina® EPIC BeadChip从妊娠<28周时采集的母血样本测量全基因组的CpG甲基化。Horvath DNAm年龄在线工具估计了AgeAccelGrim及其七个DNAm组分；正值与加速的生物老化相关，而负值相对于被试对象的年龄与生物老化速度较慢相关。主要结局为<34周的早产（任何指征）；次要结局为<37周和<28周的早产。AgeAccelGrim作为连续变量和四分位数进行分析；探索性分析评估了复合AgeAccelGrim中包含的七个DNAm组分中的每一个。数据采用卡方检验、t检验、秩和检验、逻辑回归分析（事先控制孕妇年龄、细胞计数、低社会经济地位和样本采集时的孕周），以及Kaplan-Meier生存分析进行分析；对数秩检验用于测试生存函数的相等性。共有163名患者符合纳入标准；48%分娩<37周，39%分娩<34周，21%分娩<28周。术中AgeAccelGrim中位数为-0.35（IQR -2.24, 1.31）年，对于足月分娩的患者；早产患者的AgeAccelGrim值较高，与分娩孕周成反比关系 [PTB <37 = +0.40（IQR -1.21，+2.28）年；<34 = +0.51（IQR -1.05，+2.67）年, 和<28 = +1.05（IQR -0.72，+2.72）年]。与<34周出生的早产儿相比，七个表观遗传时钟组分的DNAm估计值在具有PTB的个体中增加，尽管只有发育成纤维细胞激活抑制剂1的DNAm差异达到显著。回归模型中，AgeAccelGrim与PTB的风险升高相关，PTB的严重程度增加，其升高幅度也增加。每增加1年的AgeAccelGrim值（即相对于年龄的生物老化增加1年），PTB的调整后比值几率分别为：PTB <37周为11%（aOR 1.11，95% CI 1.00-1.24），<34周为13%（aOR 1.13，95% CI 1.01-1.26），<28周为18%（aOR 1.18，95% CI 1.04-1.35）。同样地，生物老化加速（≥75th百分位数的AgeAccelGrim）的个体在PTB<34周时，赔率比>2.36（aOR 2.36，95% CI 1.10-5.08）；在PTB <28周时，赔率比>3.89（aOR 3.89，95% CI 1.61-9.38）。PTB <37周的调整后比值为1.73，但包含零点（aOR 1.73，95% CI 0.81-3.69）。Kaplan-Meier生存分析显示，最高AgeAccelGrim四分位数的个体分娩时间最早（对数秩p<0.001）。在高风险患者中，加速的生物老化与PTB相关。未来的研究确认这些发现并阐明减缓生物老化的因素可能会改善生产结果。版权所有 © 2023. 由Elsevier Inc. 出版。

Epigenetic clocks use CpG DNA methylation (DNAm) to estimate biologic age; acceleration is associated with cancer, heart disease, and shorter lifespan. Few studies evaluate DNAm age and pregnancy outcomes. AgeAccelGrim is a novel epigenetic clock that combines seven DNAm components.We sought to determine if maternal biologic aging (via AgeAccelGrim) is associated with early PTB.A prospective cohort of patients with singleton gestations and at high risk for spontaneous preterm birth (PTB) delivering at a tertiary University hospital were included in this study. Genome-wide CpG methylation was measured using the Illumina® EPIC BeadChip from maternal blood samples obtained <28 weeks' gestation. AgeAccelGrim and its seven DNAm components were estimated by the Horvath DNAm age online tool; positive values are associated with accelerated biologic aging whereas negative values are associated with slower biologic aging relative to each subject's age. The primary outcome was PTB <34 weeks (any indication); secondary outcomes were PTB <37 and <28 weeks. AgeAccelGrim was analyzed as a continuous variable and in quartiles; exploratory analyses evaluated each of the seven DNAm components included in the composite AgeAccelGrim. Data were analyzed by chi-square, t-test, rank-sum, logistic regression (controlling a priori for maternal age, cell counts, low socioeconomic status, and gestational age at time of sample collection), and Kaplan-Meier survival analyses; the log-rank test was used to test the equality of the survival functions.163 patients met inclusion criteria; 48% delivered <37, 39% <34, and 21% <28 weeks' gestation. The median AgeAccelGrim was -0.35 (IQR -2.24, 1.31) years for those delivering at term; those delivering preterm had higher AgeAccelGrim values that were inversely proportional to delivery gestational age [PTB <37 = +0.40 (IQR -1.21, +2.28) years; <34 = +0.51 (IQR -1.05, +2.67 years, and <28 = +1.05 (IQR -0.72, +2.72) years],. Estimated DNAm of the seven epigenetic clock components values were increased among those with PTB <34 weeks' gestation, although differences were only significant for DNAm of plasminogen activation inhibitor 1. In regression models, AgeAcccelGrim was associated with an elevated risk of PTB with increasing magnitude for increasing severity of PTB. For each one-year increase in AgeAccelGrim value (ie. each one-year increase in biologic age compared to chronologic age), the adjusted odds of PTB were 11% (aOR 1.11, 95% CI 1.00-1.24), 13% (aOR 1.13, 95% CI 1.01-1.26) and 18% (aOR 1.18, 95% CI 1.04-1.35) higher for PTB <37 weeks', <34 weeks' and <28 weeks' respectively. Similarly, individuals with accelerated biologic aging (≥75th percentile AgeAccelGrim) had over double the odds of PTB <34 weeks' (aOR 2.36, 95% CI 1.10-5.08) and over triple the odds of PTB <28 weeks' (aOR 3.89, 95% CI 1.61-9.38). The adjusted odds ratio for PTB <37 weeks' gestation was 1.73, but spanned the null (aOR 1.73, 95% CI 0.81-3.69). In Kaplan-Meier survival analyses, those in the highest AgeAccelGrim quartile delivered earliest (log-rank p< 0.001).Accelerated biologic aging is associated with PTB among high-risk patients. Future research confirming these findings and elucidating factors that slow biologic aging may improve birth outcomes.Copyright © 2023. Published by Elsevier Inc.