Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies

TLDR

DNA methylation–based aging biomarkers exist for many tissues but perform poorly in fibroblasts and other ex vivo cell types, whereas strong age correlations are seen in neurons, glia, brain, liver, bone, and cord blood. The study aims to develop a robust 391‑CpG DNA‑methylation age estimator for diverse human cell types, with the goal of improving forensic and ex vivo aging assays. The authors constructed a 391‑CpG model trained on multiple human cell types to estimate epigenetic age. The skin‑and‑blood clock revealed subtle age acceleration in HGPS fibroblasts, accurately tracked ex vivo cellular aging, and linked epigenetic age to lifespan and various age‑related conditions.

Abstract

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 ex vivo 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 ex vivo 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 ex vivo human cell aging assay.