During aging, the human methylome undergoes both differential and variable shifts, accompanied by increased entropy. The distinction between variably methylated positions (VMPs) and differentially methylated positions (DMPs), their contribution to epigenetic age, and the role of cell type heterogeneity remain unclear. We conduct a comprehensive analysis of > 32,000 human blood methylomes from 56 datasets (age range = 6–101 years). We find a significant proportion of the blood methylome that is differentially methylated with age (48% DMPs; FDR < 0.005) and variably methylated with age (37% VMPs; FDR < 0.005), with considerable overlap between the two groups (59% of DMPs are VMPs). Bivalent and Polycomb regions become increasingly methylated and divergent between individuals, while quiescent regions lose methylation more uniformly. Both chronological and biological clocks, but not pace-of-aging clocks, show a strong enrichment for CpGs undergoing both mean and variance changes during aging. The accumulation of DMPs shifting towards a methylation fraction of 50% drives the increase in entropy, smoothening the epigenetic landscape. However, approximately a quarter of DMPs exhibit anti-entropic effects, opposing this direction of change. While changes in cell type composition minimally affect DMPs, VMPs and entropy measurements are moderately sensitive to such alterations. This study represents the largest investigation to date of genome-wide DNA methylation changes and aging in a single tissue, providing valuable insights into primary molecular changes relevant to chronological and biological aging.

中文翻译：

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人类衰老血液甲基化组的综合图谱


在衰老过程中，人类甲基化组经历差异性和可变性变化，并伴随着熵的增加。可变甲基化位置（VMP）和差异甲基化位置（DMP）之间的区别、它们对表观遗传年龄的贡献以及细胞类型异质性的作用仍不清楚。我们对来自 56 个数据集（年龄范围 = 6-101 岁）的 > 32,000 个人类血液甲基化组进行了全面分析。我们发现很大比例的血液甲基化组随着年龄的增长而差异甲基化（48% DMP；FDR < 0.005），并且随着年龄的变化甲基化程度不同（37% VMP；FDR < 0.005），两组之间有相当大的重叠（59 DMP 的百分比是 VMP）。二价和多梳区域的甲基化程度越来越高，个体之间的差异也越来越大，而静止区域则更均匀地失去甲基化。时间顺序和生物钟（但不是衰老速度时钟）都显示出在衰老过程中经历均值和方差变化的 CpG 的强烈富集。 DMP 的积累向 50% 的甲基化分数转变，驱动熵的增加，使表观遗传景观变得平滑。然而，大约四分之一的 DMP 表现出反熵效应，与这种变化方向相反。虽然细胞类型组成的变化对 DMP 的影响最小，但 VMP 和熵测量对此类变化具有中等敏感性。这项研究代表了迄今为止对单个组织中全基因组 DNA 甲基化变化和衰老的最大研究，为与时间和生物衰老相关的主要分子变化提供了有价值的见解。