Background

Stress contributes to premature aging and susceptibility to alcohol use disorder (AUD), and AUD itself is a factor in premature aging; however, the interrelationships of stress, AUD, and premature aging are poorly understood.

Methods

We constructed a composite score of stress from 13 stress-related outcomes in a discovery cohort of 317 individuals with AUD and control subjects. We then developed a novel methylation score of stress (MS stress) as a proxy of composite score of stress comprising 211 CpGs selected using a penalized regression model. The effects of MS stress on health outcomes and epigenetic aging were assessed in a sample of 615 patients with AUD and control subjects using epigenetic clocks and DNA methylation–based telomere length. Statistical analysis with an additive model using MS stress and a MS for alcohol consumption (MS alcohol) was conducted. Results were replicated in 2 independent cohorts (Generation Scotland, N = 7028 and the Grady Trauma Project, N = 795).

Results

Composite score of stress and MS stress were strongly associated with heavy alcohol consumption, trauma experience, epigenetic age acceleration (EAA), and shortened DNA methylation–based telomere length in AUD. Together, MS stress and MS alcohol additively showed strong stepwise increases in EAA. Replication analyses showed robust association between MS stress and EAA in the Generation Scotland and Grady Trauma Project cohorts.

Conclusions

A methylation-derived score tracking stress exposure is associated with various stress-related phenotypes and EAA. Stress and alcohol have additive effects on aging, offering new insights into the pathophysiology of premature aging in AUD and, potentially, other aspects of gene dysregulation in this disorder.

中文翻译：

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压力和酒精暴露对酒精使用障碍加速表观遗传老化的累加效应

背景

压力会导致过早衰老和易患酒精使用障碍 (AUD)，而 AUD 本身就是过早衰老的一个因素；然而，人们对压力、澳元和过早衰老之间的相互关系知之甚少。

方法

我们从 317 名患有 AUD 和对照受试者的发现队列中的 13 项压力相关结果构建了压力综合评分。然后，我们开发了一种新的压力甲基化评分（MS 压力）作为压力综合评分的代表，包括使用惩罚回归模型选择的 211 个 CpG。使用表观遗传时钟和基于 DNA 甲基化的端粒长度，在 615 名 AUD 患者和对照受试者的样本中评估了 MS 压力对健康结果和表观遗传衰老的影响。使用 MS 压力和酒精消耗量（MS 酒精）的 MS 进行加法模型的统计分析。结果在 2 个独立队列中重复（苏格兰一代，N  = 7028 和 Grady Trauma 项目，N  = 795）。

结果

压力和 MS 压力的综合评分与重度饮酒、创伤经历、表观遗传年龄加速 (EAA) 和 AUD 中基于 DNA 甲基化的端粒长度缩短密切相关。MS 压力和 MS 酒精相加地显示出 EAA 的强烈逐步增加。复制分析显示，在苏格兰一代和格雷迪创伤项目队列中，MS 压力与 EAA 之间存在稳固关联。

结论

跟踪压力暴露的甲基化衍生评分与各种压力相关表型和 EAA 相关。压力和酒精对衰老具有累加效应，为 AUD 过早衰老的病理生理学以及该疾病中基因失调的其他潜在方面提供了新的见解。