Psychiatric stress has been associated with accelerated epigenetic aging (i.e., when estimates of cellular age based on DNA methylation exceed chronological age) in both blood and brain tissue. Little is known about the downstream biological effects of accelerated epigenetic age on gene expression. In this study we examined associations between DNA methylation-derived estimates of cellular age that range from decelerated to accelerated relative to chronological age (“DNAm age residuals”) and transcriptome-wide gene expression. This was examined using tissue from three post-mortem cortical regions (ventromedial and dorsolateral prefrontal cortex and motor cortex, n = 97) from the VA National PTSD Brain Bank. In addition, we examined how posttraumatic stress disorder (PTSD) and alcohol-use disorders (AUD) moderated the association between DNAm age residuals and gene expression. Transcriptome-wide results across brain regions, psychiatric diagnoses, and cohorts (full sample and male and female subsets) revealed experiment-wide differential expression of 11 genes in association with PTSD or AUD in interaction with DNAm age residuals. This included the inflammation-related genes IL1B, RCOR2, and GCNT1. Candidate gene class analyses and gene network enrichment analyses further supported differential expression of inflammation/immune gene networks as well as glucocorticoid, circadian, and oxidative stress-related genes. Gene co-expression network modules suggested enrichment of myelination related processes and oligodendrocyte enrichment in association with DNAm age residuals in the presence of psychopathology. Collectively, results suggest that psychiatric stress accentuates the association between advanced epigenetic age and expression of inflammation genes in the brain. This highlights the role of inflammatory processes in the pathophysiology of accelerated cellular aging and suggests that inflammatory pathways may link accelerated cellular aging to premature disease onset and neurodegeneration, particularly in stressed populations. This suggests that anti-inflammatory interventions may be an important direction to pursue in evaluating ways to prevent or delay cellular aging and increase resilience to diseases of aging.

精神压力与血液和脑组织中加速的表观遗传衰老（即，当基于 DNA 甲基化的细胞年龄估计超过实际年龄）有关。关于加速表观遗传年龄对基因表达的下游生物学影响知之甚少。在这项研究中，我们检查了 DNA 甲基化衍生的细胞年龄估计值（相对于实足年龄从减速到加速）与转录组范围内的基因表达之间的关联。使用来自三个死后皮层区域（腹内侧和背外侧前额叶皮层和运动皮层，n = 97) 来自 VA 国家 PTSD 脑库。此外，我们研究了创伤后应激障碍 (PTSD) 和酒精使用障碍 (AUD) 如何调节 DNAm 年龄残留物与基因表达之间的关联。跨大脑区域、精神病学诊断和队列（完整样本和男性和女性子集）的全转录组结果揭示了 11 个与 PTSD 或 AUD 相关的基因与 DNAm 年龄残差相互作用的全实验差异表达。这包括炎症相关基因IL1B、RCOR2和GCNT1. 候选基因类别分析和基因网络富集分析进一步支持炎症/免疫基因网络以及糖皮质激素、昼夜节律和氧化应激相关基因的差异表达。基因共表达网络模块表明，在精神病理学存在的情况下，髓鞘形成相关过程和少突胶质细胞富集与 DNAm 年龄残基相关。总的来说，结果表明精神压力强调了高龄表观遗传年龄与大脑中炎症基因表达之间的关联。这突出了炎症过程在加速细胞衰老的病理生理学中的作用，并表明炎症途径可能将加速细胞衰老与过早疾病发作和神经变性联系起来，特别是在压力大的人群中。