DNA methylation age of human tissues and cell types

TLDR

It is not yet known whether DNA methylation levels can accurately predict age across diverse human tissues and cell types, or whether the resulting age prediction is biologically meaningful. The study develops a multi‑tissue DNA methylation age predictor, proposes that it reflects cumulative epigenetic maintenance, and aims to enable research in development, cancer, and aging. The predictor was built from 8,000 samples across 82 Illumina methylation array datasets covering 51 healthy tissues and cell types. DNA methylation age is near zero in embryonic and iPSC cells, correlates with passage number, is highly heritable, applies to chimp tissues, and shows significant age acceleration in cancers (average 36 years), with low acceleration linked to many somatic mutations and TP53 mutations, while steroid receptor mutations strongly accelerate age in breast cancer.

Abstract

It is not yet known whether DNA methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulting age prediction is a biologically meaningful measure.I developed a multi-tissue predictor of age that allows one to estimate the DNA methylation age of most tissues and cell types. The predictor, which is freely available, was developed using 8,000 samples from 82 Illumina DNA methylation array datasets, encompassing 51 healthy tissues and cell types. I found that DNA methylation age has the following properties: first, it is close to zero for embryonic and induced pluripotent stem cells; second, it correlates with cell passage number; third, it gives rise to a highly heritable measure of age acceleration; and, fourth, it is applicable to chimpanzee tissues. Analysis of 6,000 cancer samples from 32 datasets showed that all of the considered 20 cancer types exhibit significant age acceleration, with an average of 36 years. Low age-acceleration of cancer tissue is associated with a high number of somatic mutations and TP53 mutations, while mutations in steroid receptors greatly accelerate DNA methylation age in breast cancer. Finally, I characterize the 353 CpG sites that together form an aging clock in terms of chromatin states and tissue variance.I propose that DNA methylation age measures the cumulative effect of an epigenetic maintenance system. This novel epigenetic clock can be used to address a host of questions in developmental biology, cancer and aging research.