DNA甲基化导致的年龄加速揭示了抑郁症和自杀的神经发育和压力相关途径
DNA methylation-derived age acceleration reveals neurodevelopmental and stress-linked pathways in depression and suicide.
摘要(中文译文)
重性抑郁障碍（MDD）与包括自杀在内的过早死亡风险显著增加相关，然而将抑郁与寿命缩短联系起来的生物学机制仍知之甚少。新兴证据表明，以DNA甲基化为基础的表观遗传时钟所测量的加速生物学衰老，是导致这一死亡率差距的关键因素。我们采用多种DNA甲基化时钟（Horvath、Hannum和GrimAge）检测了自杀死亡（MDD+S）或因非自杀原因死亡的个体背外侧前额叶皮层（dlPFC）中的表观遗传衰老，提供了一种直接且具有生物学意义的神经衰老测量指标。对于每个年龄加速指标，我们使用DMRcate识别差异甲基化区域（DMR），要求至少包含10个CpG位点、FDR<0.05且甲基化差异达到5%。所有时钟均与实足年龄呈强相关，其中GrimAge表现出最高的一致性（r=0.96，p<2×10）。在不同表观遗传年龄加速指标的协变量校正回归模型中，分组与AgeAccelGrim显著相关，物质滥用也是一个显著的预测因子。与高表观遗传年龄加速相比低表观遗传年龄加速相关的DMR识别出时钟特异性和重叠的基因组位点，富集于调控神经前体增殖、Rho-GTPase信号传导和smoothened（Hedgehog）通路调节的通路中。这些发现表明，抑郁和自杀中加速或失调的表观遗传衰老可能通过神经发育和神经可塑性相关甲基化网络的改变而表现出来，反映了对应激敏感的生物学过程，这些过程促进了心境障碍的严重程度和自杀易感性。
Abstract
Major Depressive Disorder (MDD) is associated with markedly increased risk of premature mortality, including suicide, yet the biological mechanisms linking depression to reduced lifespan remain poorly understood. Emerging evidence suggests that accelerated biological aging, as measured by DNA methylation-based epigenetic clocks, is a key contributor to this mortality gap. We examined epigenetic aging in the dorsolateral prefrontal cortex (dlPFC) from individuals who died by suicide (MDD + S) or by causes other than suicide, using multiple DNA methylation clocks (Horvath, Hannum, and GrimAge), providing a direct and biologically meaningful measure of neural aging. For each age acceleration, we used DMRcate to identify differentially methylated regions (DMR) with at least 10 CpGs, an FDR <0.05, and a 5% methylation difference. All clocks exhibited strong correlations with chronological age, with GrimAge showing the highest concordance (r = 0.96, p < 2 × 10). In covariate-adjusted regression models across different epigenetic age acceleration measures, group was significantly associated with AgeAccelGrim, and substance abuse was also a significant predictor. DMRs associated with high versus low epigenetic age acceleration identified clock-specific and overlapping genomic loci, enriched in pathways governing neural precursor proliferation, Rho-GTPase signaling, and smoothened (Hedgehog) pathway regulation. The findings indicate that accelerated or dysregulated epigenetic aging in depression and suicide may manifest through alterations in neurodevelopmental and neuroplasticity-related methylation networks, reflecting stress-sensitive biological processes that contribute to mood disorder severity and suicide vulnerability.
如何引用
AMA
Aleena Francis, Yogesh Dwivedi. DNA methylation-derived age acceleration reveals neurodevelopmental and stress-linked pathways in depression and suicide.. Journal of affective disorders. 2026; doi:10.1016/j.jad.2026.121881.
APA
Aleena Francis, Yogesh Dwivedi (2026). DNA methylation-derived age acceleration reveals neurodevelopmental and stress-linked pathways in depression and suicide.. Journal of affective disorders. https://doi.org/10.1016/j.jad.2026.121881
GB/T 7714
Aleena Francis, Yogesh Dwivedi. DNA methylation-derived age acceleration reveals neurodevelopmental and stress-linked pathways in depression and suicide.[J]. Journal of affective disorders, 2026 doi:10.1016/j.jad.2026.121881.
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