ImportanceAll-cause mortality and the risk for age-related medical disease is increased in individuals with psychiatric illness, but the underlying biological mechanisms are not known. Oxidative stress on nucleic acids (DNA and RNA; NA-OXS) is a molecular driver of aging and a potential pathophysiological mechanism in a range of age-related disorders.ObjectiveTo study the levels of markers of NA-OXS in a large cohort of community-dwelling individuals with and without psychiatric illness and to evaluate their association with prospective all-cause mortality.Design, Setting, and ParticipantsThis cohort study used a combined cohort of participants from 2 population-based health studies: the Danish General Suburban Population Study (January 2010 to October 2013) and nondiabetic control participants from the Vejle Diabetes Biobank study (March 2007 to May 2010). Individual history of psychiatric illness was characterized using register data on psychiatric diagnoses and use of psychotropic drugs before baseline examination. Urinary markers of systemic RNA (8-oxo-7,8-dihydroguanosine [8-oxoGuo]) and DNA (8-oxo-7,8-dihydro-2’-deoxyguanosine [8-oxodG]) damage from oxidation were measured by ultraperformance liquid chromatography–tandem mass spectrometry. Cox proportional hazard regression models were applied for survival analyses, using register-based all-cause mortality updated to May 2023. The follow-up time was up to 16.0 years.ExposuresHistory of psychiatric illness.Main Outcomes and MeasuresMortality risk according to psychiatric illness status and 8-oxoGuo or 8-oxodG excretion level.ResultsA total of 7728 individuals were included (3983 [51.5%] female; mean [SD] age, 58.6 [11.9] years), 3095 of whom (40.0%) had a history of psychiatric illness. Mean (SD) baseline 8-oxoGuo was statistically significantly higher in individuals with psychiatric illness than in those without (2.4 [1.2] nmol/mmol vs 2.2 [0.9] nmol/mmol; P < .001), whereas 8-oxodG was not. All-cause mortality was higher in the psychiatric illness group vs the no psychiatric illness group (hazard ratio [HR], 1.44; 95% CI, 1.27-1.64; P < .001) and increased sequentially with each increasing tertile of 8-oxoGuo excretion in both groups to an almost doubled risk in the psychiatric illness/high 8-oxoGuo group compared to the no psychiatric illness/low 8-oxoGuo reference group (HR, 1.99; 95% CI, 1.58-2.52; P < .001). These results persisted after adjustment for a range of potential confounders and in a sensitivity analysis stratified for sex.Conclusions and RelevanceThis study establishes systemic oxidative stress-induced damage to RNA as a potential mechanism in the accelerated aging observed in psychiatric disorders and urinary 8-oxoGuo as a potentially useful marker of mortality risk in individuals with psychiatric illness.

中文翻译：

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氧化应激引起的 RNA 和 DNA 损伤以及精神疾病患者的死亡率

重要性：患有精神疾病的个体的全因死亡率和与年龄相关的疾病的风险会增加，但其潜在的生物学机制尚不清楚。核酸（DNA 和 RNA；NA-OXS）的氧化应激是衰老的分子驱动因素，也是一系列与年龄相关的疾病的潜在病理生理机制。目的研究大量社区中 NA-OXS 标记物的水平-患有或不患有精神疾病的居住个体，并评估其与预期全因死亡率的关系。设计、设置和参与者本队列研究使用了来自两项基于人口的健康研究的参与者组合队列：丹麦一般郊区人口研究（1 月） 2010 年至 2013 年 10 月）和来自瓦埃勒糖尿病生物库研究（2007 年 3 月至 2010 年 5 月）的非糖尿病对照参与者。使用基线检查前精神病诊断和精神药物使用的登记数据来表征个体精神疾病史。氧化引起的全身性 RNA（8-oxo-7,8-二氢鸟苷 [8-oxoGuo]）和 DNA（8-oxo-7,8-二氢-2'-脱氧鸟苷 [8-oxodG]）损伤的尿液标记物通过以下方法测量超高效液相色谱-串联质谱法。应用 Cox 比例风险回归模型进行生存分析，使用更新至 2023 年 5 月的基于登记的全因死亡率。随访时间长达 16.0 年。暴露精神疾病史。主要结果和措施根据精神疾病状态的死亡率风险和 8-oxoGuo 或 8-oxodG 排泄水平。 结果 总共纳入 7728 名个体（3983 [51.5%] 女性；平均 [SD] 年龄，58.6 [11.9] 岁），其中 3095 名（40.0%）有既往史精神疾病。患有精神疾病的个体的平均（SD）基线8-oxoGuo在统计学上显着高于没有精神疾病的个体（2.4 [1.2] nmol/mmol vs 2.2 [0.9] nmol/mmol；磷< .001)，而 8-oxodG 则不然。精神疾病组的全因死亡率高于无精神疾病组（风险比 [HR]，1.44；95% CI，1.27-1.64；磷< .001），并且随着两组中 8-oxoGuo 排泄量每增加一个三分位数，精神疾病/高 8-oxoGuo 组的风险几乎是无精神疾病/低 8-oxoGuo 参考组的两倍（HR，1.99） ；95% CI，1.58-2.52；磷< .001）。在调整了一系列潜在的混杂因素以及按性别分层的敏感性分析后，这些结果仍然存在。结论和相关性本研究确立了全身氧化应激诱导的 RNA 损伤作为精神疾病和尿 8-oxoGuo 中观察到的加速衰老的潜在机制。作为精神疾病患者死亡风险的潜在有用标志。