Zillich Lea, Cetin Metin, Hummel Elisabeth M, Poisel Eric, Fries Gabriel R, Frank Josef, Streit Fabian, Foo Jerome C, Sirignano Lea, Friske Marion M, Lenz Bernd, Hoffmann Sabine, Adorjan Kristina, Kiefer Falk, Bakalkin Georgy, Hansson Anita C, Lohoff Falk W, Kärkkäinen Olli, Kok Eloise, Karhunen Pekka J, Sutherland Greg T, Walss-Bass Consuelo, Spanagel Rainer, Rietschel Marcella, Moser Dirk A, Witt Stephanie H
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
Alcohol Clin Exp Res (Hoboken). 2024 Feb;48(2):250-259. doi: 10.1111/acer.15241. Epub 2024 Jan 26.
Alcohol use disorder (AUD) is associated with increased mortality and morbidity risk. A reason for this could be accelerated biological aging, which is strongly influenced by disease processes such as inflammation. As recent studies of AUD show changes in DNA methylation and gene expression in neuroinflammation-related pathways in the brain, biological aging represents a potentially important construct for understanding the adverse effects of substance use disorders. Epigenetic clocks have shown accelerated aging in blood samples from individuals with AUD. However, no systematic evaluation of biological age measures in AUD across different tissues and brain regions has been undertaken.
As markers of biological aging (BioAge markers), we assessed Levine's and Horvath's epigenetic clocks, DNA methylation telomere length (DNAmTL), telomere length (TL), and mitochondrial DNA copy number (mtDNAcn) in postmortem brain samples from Brodmann Area 9 (BA9), caudate nucleus, and ventral striatum (N = 63-94), and in whole blood samples (N = 179) of individuals with and without AUD. To evaluate the association between AUD status and BioAge markers, we performed linear regression analyses while adjusting for covariates.
The majority of BioAge markers were significantly associated with chronological age in all samples. Levine's epigenetic clock and DNAmTL were indicative of accelerated biological aging in AUD in BA9 and whole blood samples, while Horvath's showed the opposite effect in BA9. No significant association of AUD with TL and mtDNAcn was detected. Measured TL and DNAmTL showed only small correlations in blood and none in brain.
The present study is the first to simultaneously investigate epigenetic clocks, telomere length, and mtDNAcn in postmortem brain and whole blood samples in individuals with AUD. We found evidence for accelerated biological aging in AUD in blood and brain, as measured by Levine's epigenetic clock, and DNAmTL. Additional studies of different tissues from the same individuals are needed to draw valid conclusions about the congruence of biological aging in blood and brain.
酒精使用障碍（AUD）与死亡率和发病率风险增加相关。其原因之一可能是生物衰老加速，而生物衰老受炎症等疾病过程的强烈影响。近期对AUD的研究表明，大脑中神经炎症相关通路的DNA甲基化和基因表达发生了变化，生物衰老代表了理解物质使用障碍不良影响的一个潜在重要概念。表观遗传时钟已显示AUD个体血液样本中的衰老加速。然而，尚未对AUD患者不同组织和脑区的生物年龄测量进行系统评估。
作为生物衰老的标志物（生物年龄标志物），我们评估了来自布罗德曼区9（BA9）、尾状核和腹侧纹状体的尸检脑样本（N = 63 - 94）以及有和无AUD个体的全血样本（N = 179）中的莱文斯和霍瓦斯表观遗传时钟、DNA甲基化端粒长度（DNAmTL）、端粒长度（TL）和线粒体DNA拷贝数（mtDNAcn）。为了评估AUD状态与生物年龄标志物之间的关联，我们在调整协变量的同时进行了线性回归分析。
在所有样本中，大多数生物年龄标志物与实际年龄显著相关。莱文斯表观遗传时钟和DNAmTL表明BA9和全血样本中AUD患者的生物衰老加速，而霍瓦斯表观遗传时钟在BA9中显示出相反的效果。未检测到AUD与TL和mtDNAcn之间的显著关联。测得的TL和DNAmTL在血液中仅显示出微弱的相关性，在大脑中则无相关性。
本研究首次同时调查了AUD个体尸检脑和全血样本中的表观遗传时钟、端粒长度和mtDNAcn。我们发现，通过莱文斯表观遗传时钟和DNAmTL测量，AUD患者的血液和大脑中存在生物衰老加速的证据。需要对同一患者的不同组织进行更多研究，以得出关于血液和大脑中生物衰老一致性的有效结论。
