It has been noted for quite some time that DNA methylation levels decline with age. The significance of this change remained unknown until it became possible to measure methylation status of specific sites on the DNA. It was observed that while the methylation of some sites does indeed decrease with age, that of others increase or remain unchanged. The application of machine learning methods to these quantitative changes in multiple sites, allowed the generation of a highly accurate estimator of age, called the epigenetic clock. The application of this clock on large human epidemiological data sets revealed that discordance between the predicted (epigenetic age) and chronological age is associated with many age-related pathologies, particularly when the former is greater than the latter. The epigenetic clock clearly captures to some degree, biological features that accompany the ageing process. Despite the ever-increasing scope of pathologies that are found to be associated with accelerated epigenetic ageing, the basic principles that underlie the ticking of the clock remain elusive. Here, we describe the known molecular and cellular attributes of the clock and consider their properties, and proffer opinions as to how they may be connected and what might be the underlying mechanism. Emerging from these considerations is the inescapable view that epigenetic ageing begins from very early moments after the embryonic stem cell stage and continues un-interrupted through the entire life-course. This appears to be a consequence of processes that are necessary for the development of the organism from conception and to maintain it thereafter through homeostasis. Hence, while the speed of ageing can, and is affected by external factors, the essence of the ageing process itself is an integral part of, and the consequence of the development of life.

Impact statement

The field of epigenetic ageing is relatively new, and the speed of its expansion presents a challenge in keeping abreast with new discoveries and their implications. Several reviews have already addressed the great number of pathologies, health conditions, life-style, and external stressors that are associated with changes to the rate of epigenetic ageing. While these associations highlight and affirm the ability of epigenetic clock to capture biologically meaningful changes associated with age, they do not inform us about the underlying mechanisms. In this very early period since the development of the clock, there have been rather limited experimental research that are aimed at uncovering the mechanism. Hence, the perspective that we proffer is derived from available but nevertheless limited lines of evidence that together provide a seemingly coherent narrative that can be tested. This, we believe would be helpful towards uncovering the workings of the epigenetic clock.

中文翻译：

---

当前对表观遗传衰老的细胞和分子特征的看法。

人们已经注意到 DNA 甲基化水平随着年龄的增长而下降。在可以测量 DNA 上特定位点的甲基化状态之前，这种变化的重要性仍然未知。据观察，虽然某些位点的甲基化确实随着年龄的增长而减少，但其他位点的甲基化却增加或保持不变。将机器学习方法应用于多个地点的这些数量变化，可以生成高度准确的年龄估计值，称为表观遗传时钟。该时钟在大型人类流行病学数据集上的应用表明，预测（表观遗传年龄）和实足年龄之间的不一致与许多与年龄相关的病理有关，尤其是当前者大于后者时。表观遗传时钟在某种程度上清楚地捕捉到，伴随衰老过程的生物学特征。尽管发现与加速表观遗传衰老相关的病理范围不断扩大，但构成时钟滴答作响的基本原理仍然难以捉摸。在这里，我们描述了时钟的已知分子和细胞属性，并考虑了它们的特性，并就它们如何连接以及可能是什么潜在机制提出了意见。从这些考虑中得出的观点是，表观遗传衰老从胚胎干细胞阶段后的很早时刻开始，并在整个生命过程中不间断地持续。这似乎是有机体从受孕开始发育并在此后通过体内平衡维持它所必需的过程的结果。因此，

影响陈述

表观遗传衰老领域相对较新，其扩张速度对跟上新发现及其影响提出了挑战。一些评论已经解决了与表观遗传衰老速度变化相关的大量病理、健康状况、生活方式和外部压力因素。虽然这些关联突出并肯定了表观遗传时钟捕捉与年龄相关的生物学意义变化的能力，但它们并没有告诉我们潜在的机制。在自时钟开发以来的这个非常早期的时期，旨在揭示该机制的实验研究相当有限。因此，我们提供的观点来自现有但有限的证据，这些证据共同提供了一个看似连贯的叙述，可以进行测试。我们相信这将有助于揭示表观遗传时钟的工作原理。