Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, 1941 East Rd, 77054, Houston, TX, USA.
Department of Neuroscience and Pharmacology, The University of Iowa, 51 Newton Rd, 52242, Iowa City, IA, USA.
Neuropsychopharmacology. 2023 May;48(6):954-962. doi: 10.1038/s41386-023-01557-9. Epub 2023 Mar 6.
Bipolar disorder (BD) has been previously associated with premature mortality and aging, including acceleration of epigenetic aging. Suicide attempts (SA) are greatly elevated in BD and are associated with decreased lifespan, biological aging, and poorer clinical outcomes. We investigated the relationship between GrimAge, an epigenetic clock trained on time-to-death and associated with mortality and lifespan, and SA in two independent cohorts of BD individuals (discovery cohort - controls (n = 50), BD individuals with (n = 77, BD/SA) and without (n = 67, BD/non-SA) lifetime history of SA; replication cohort - BD/SA (n = 48) and BD/non-SA (n = 47)). An acceleration index for the GrimAge clock (GrimAgeAccel) was computed from blood DNA methylation (DNAm) and compared between groups with multiple general linear models. Differences in epigenetic aging from the discovery cohort were validated in the independent replication cohort. In the discovery cohort, controls, BD/non-SA, and BD/SA significantly differed on GrimAgeAccel (F = 5.424, p = 0.005), with the highest GrimAgeAccel in BD/SA (p = 0.004, BD/SA vs. controls). Within the BD individuals, BD/non-SA and BD/SA differed on GrimAgeAccel in both cohorts (p = 0.008) after covariate adjustment. Finally, DNAm-based surrogates revealed possible involvement of plasminogen activator inhibitor 1, leptin, and smoking pack-years in driving accelerated epigenetic aging. These findings pair with existing evidence that not only BD, but also SA, may be associated with an accelerated biological aging and provide putative biological mechanisms for morbidity and premature mortality in this population.
双相情感障碍 (BD) 以前与过早死亡和衰老有关，包括表观遗传衰老的加速。自杀未遂 (SA) 在 BD 中大大增加，与寿命缩短、生物衰老和较差的临床结局有关。我们在两个独立的 BD 个体队列中研究了 GrimAge（一种基于死亡时间训练的表观遗传时钟，与死亡率和寿命相关）与 SA 之间的关系（发现队列-对照组 (n = 50)，BD 个体中有 (n = 77, BD/SA) 和没有 (n = 67, BD/non-SA) 一生中的自杀未遂史；复制队列-BD/SA (n = 48) 和 BD/non-SA (n = 47)）。从血液 DNA 甲基化 (DNAm) 计算 GrimAge 时钟的加速指数 (GrimAgeAccel)，并使用多个一般线性模型在组间进行比较。从发现队列中得出的表观遗传衰老差异在独立的复制队列中得到验证。在发现队列中，对照、BD/non-SA 和 BD/SA 在 GrimAgeAccel 上存在显著差异（F = 5.424，p = 0.005），BD/SA 的 GrimAgeAccel 最高（p = 0.004，BD/SA 与对照）。在 BD 个体中，BD/non-SA 和 BD/SA 在两个队列中都存在 GrimAgeAccel 差异（p = 0.008），经过协变量调整。最后，基于 DNAm 的替代物表明，纤溶酶原激活物抑制剂 1、瘦素和吸烟包年可能参与驱动加速的表观遗传衰老。这些发现与现有的证据一致，即不仅 BD，而且 SA，可能与加速的生物衰老有关，并为该人群的发病率和过早死亡提供了潜在的生物学机制。
