Properties of the epigenetic clock and age acceleration
Properties of the epigenetic clock and age acceleration
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DOI：
10.1101/363143
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发表时间：
2018-07
期刊：
影响因子：
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通讯作者：
L. Khoury;T. Gorrie-stone;M. Smart;A. Hughes;Y. Bao;Alexandria Andrayas;Joe Burrage;E. Hannon
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文献类型：
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作者：
L. Khoury;T. Gorrie-stone;M. Smart;A. Hughes;Y. Bao;Alexandria Andrayas;Joe Burrage;E. Hannon
背景 人类基因组中众多 CpG 位点的甲基化状态随年龄而变化。 Horvath 表观遗传时钟使用各种已发表的 DNA 甲基化数据来生成年龄预测，该预测已广泛用于预测未知样本中的年龄，并得出有关各种组织、环境和疾病的衰老速度的结论。尽管该模型很实用，但仍有许多假设需要检验。我们探索了老年人的全血和多个大脑区域的模型特征，这些老年人在原始训练数据中没有得到很好的体现，以及来自横断面人口研究的血液中的模型特征。结果我们发现该模型系统地低估了老年人组织的年龄。在大约 60 岁时观察到预测年龄的斜率下降，这表明模型中的一些基因座可能会随着年龄的增长而发生不同的变化，并且年龄加速测量本身将取决于年龄。这种现象在小脑中最为明显，但也存在于其他检查组织中，并且在多个数据集中一致观察到。当将年龄用作协变量时，阿尔茨海默病与年龄加速的明显关联就消失了。文献中的关联检验使用多种方法来计算年龄加速，并且通常不使用年龄作为协变量。这是误导性发现的潜在原因。结论 应谨慎评估表型与年龄加速的关联，并且将实际年龄作为协变量纳入所有分析中。
Background The methylation status of numerous CpG sites in the human genome varies with age. The Horvath epigenetic clock used a wide variety of published DNA methylation data to produce an age prediction that has been widely used to, predict age in unknown samples, and draw conclusions about speed of ageing in various tissues, environments, and diseases. Despite its utility, there are a number of assumptions in the model that require examination. We explore the characteristics of the model in whole blood and multiple brain regions from older people, who are not well represented in the original training data, and in blood from a cross-sectional population study. Results We find that the model systematically underestimates age in tissues from older people. A decrease in slope of the predicted ages were observed at approximately 60 years, indicating that some loci in the model may change differently with age, and that age acceleration measures will themselves be age-dependent. This is seen most strongly in the cerebellum but is also present in other examined tissues, and is consistently observed in multiple datasets. An apparent association of Alzheimer’s disease with age acceleration disappears when age is used as a covariate. Association tests in the literature use a variety of methods for calculating age acceleration and often do not use age as a covariate. This is a potential cause of misleading findings. Conclusions Associations of phenotypes with age acceleration should be evaluated cautiously, and chronological age should be included as a covariate in all analyses.