Horvath Steve, Oshima Junko, Martin George M, Lu Ake T, Quach Austin, Cohen Howard, Felton Sarah, Matsuyama Mieko, Lowe Donna, Kabacik Sylwia, Wilson James G, Reiner Alex P, Maierhofer Anna, Flunkert Julia, Aviv Abraham, Hou Lifang, Baccarelli Andrea A, Li Yun, Stewart James D, Whitsel Eric A, Ferrucci Luigi, Matsuyama Shigemi, Raj Kenneth
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Department of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA.
Aging (Albany NY). 2018 Jul 26;10(7):1758-1775. doi: 10.18632/aging.101508.
DNA methylation (DNAm)-based biomarkers of aging have been developed for many tissues and organs. However, these biomarkers have sub-optimal accuracy in fibroblasts and other cell types used in studies. To address this challenge, we developed a novel and highly robust DNAm age estimator (based on 391 CpGs) for human fibroblasts, keratinocytes, buccal cells, endothelial cells, lymphoblastoid cells, skin, blood, and saliva samples. High age correlations can also be observed in sorted neurons, glia, brain, liver, and even bone samples. Gestational age correlates with DNAm age in cord blood. When used on fibroblasts from Hutchinson Gilford Progeria Syndrome patients, this age estimator (referred to as the skin & blood clock) uncovered an epigenetic age acceleration with a magnitude that is below the sensitivity levels of other DNAm-based biomarkers. Furthermore, this highly sensitive age estimator accurately tracked the dynamic aging of cells cultured and revealed that their proliferation is accompanied by a steady increase in epigenetic age. The skin & blood clock predicts lifespan and it relates to many age-related conditions. Overall, this biomarker is expected to become useful for forensic applications (e.g. blood or buccal swabs) and for a quantitative human cell aging assay.
基于DNA甲基化(DNAm)的衰老生物标志物已针对许多组织和器官开发出来。然而,这些生物标志物在成纤维细胞和研究中使用的其他细胞类型中的准确性欠佳。为应对这一挑战,我们针对人类成纤维细胞、角质形成细胞、颊细胞、内皮细胞、淋巴母细胞、皮肤、血液和唾液样本开发了一种新型且高度稳健的DNAm年龄估计器(基于391个CpG)。在分选的神经元、神经胶质细胞、大脑、肝脏甚至骨骼样本中也能观察到高度的年龄相关性。胎龄与脐带血中的DNAm年龄相关。当应用于哈钦森 - 吉尔福德早衰综合征患者的成纤维细胞时,这种年龄估计器(称为皮肤与血液时钟)揭示了一种表观遗传年龄加速,其程度低于其他基于DNAm的生物标志物的敏感水平。此外,这种高度敏感的年龄估计器准确地跟踪了培养细胞的动态衰老,并表明它们的增殖伴随着表观遗传年龄的稳步增加。皮肤与血液时钟可预测寿命,且与许多与年龄相关的状况有关。总体而言,这种生物标志物有望用于法医应用(如血液或颊拭子)以及定量人类细胞衰老检测。