BACKGROUND Schizophrenia (SZ) is associated with increased all-cause mortality, smoking, and age-associated proteins, yet multiple previous studies found no association between SZ and biological age using Horvath's epigenetic clock, a well-established aging biomarker based on DNA methylation. However, numerous epigenetic clocks that may capture distinct aspects of aging have been developed. This study tested the hypothesis that altered aging in SZ manifests in these other clocks. METHODS We performed a comprehensive analysis of 14 epigenetic clocks categorized according to what they were trained to predict: chronological age, mortality, mitotic divisions, or telomere length. To understand the etiology of biological age differences, we also examined DNA methylation predictors of smoking, alcohol, body mass index, serum proteins, and cell proportions. We independently analyzed 3 publicly available multiethnic DNA methylation data sets from whole blood, a total of 567 SZ cases and 594 nonpsychiatric controls. RESULTS All data sets showed accelerations in SZ for the 3 mortality clocks up to 5 years, driven by smoking and elevated levels of 6 age-associated proteins. The 2 mitotic clocks were decelerated in SZ related to antitumor natural killer and CD8T cells, which may help explain conflicting reports about low cancer rates in epidemiological studies of SZ. One cohort with available medication data showed that clozapine is associated with male-specific decelerations up to 7 years in multiple chronological age clocks. CONCLUSIONS Our study demonstrates the utility of studying the various epigenetic clocks in tandem and highlights potential mechanisms by which mental illness influences long-term outcomes, including cancer and early mortality.

中文翻译：

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精神分裂症和表观遗传衰老生物标志物：死亡率增加、癌症风险降低以及氯氮平的独特作用

背景精神分裂症 (SZ) 与全因死亡率、吸烟和年龄相关蛋白增加有关，但之前的多项研究发现，使用 Horvath 的表观遗传时钟（一种基于 DNA 甲基化的成熟衰老生物标志物），SZ 与生物年龄之间没有关联。然而，已经开发出许多可以捕捉衰老不同方面的表观遗传时钟。这项研究检验了深圳衰老现象在其他生物钟中表现出来的改变这一假设。方法 我们对 14 个表观遗传时钟进行了全面分析，这些表观遗传时钟根据它们经过训练的预测内容进行分类：实际年龄、死亡率、有丝分裂或端粒长度。为了了解生物年龄差异的病因学，我们还检查了吸烟、饮酒、体重指数、血清蛋白和细胞比例的 DNA 甲基化预测因子。我们独立分析了 3 个公开的全血多种族 DNA 甲基化数据集，总共 567 例 SZ 病例和 594 例非精神病对照。结果 所有数据集均显示，在吸烟和 6 种与年龄相关的蛋白质水平升高的推动下，SZ 在长达 5 年的 3 个死亡率时钟中加速。SZ 中与抗肿瘤自然杀伤细胞和 CD8T 细胞相关的 2 个有丝分裂时钟减慢，这可能有助于解释关于 SZ 流行病学研究中癌症发病率低的相互矛盾的报告。一组可用的药物数据表明，氯氮平与多个年龄时钟中长达 7 岁的男性特异性减慢有关。结论我们的研究证明了串联研究各种表观遗传时钟的实用性，并强调了精神疾病影响长期结果（包括癌症和早期死亡率）的潜在机制。