Loss of cell-identity DNA methylation tracks division history, not DNA damage

In human skin fibroblasts, loss of cell-identity DNA methylation tracks prolonged division history, with replicative exhaustion costing 24.3% (95% CI 20.2–28.7) of identity information.

• Why it matters: A key aging model proposes DNA damage degrades the epigenome and erases cell-identity information, but direct tests using cell-type-unique CpGs are needed.
• What they did: The study built a panel of 9,150 fibroblast-unique CpGs versus 20 primary cell types, then quantified identity loss using Bernoulli cross-entropy across 24 matched fibroblast cultures under perturbations.
• The result: Replicative exhaustion (24.3%) and RAS activation (5.4%) reduced identity information, while a senescence-inducing X-ray dose showed −0.5% (−0.7 to −0.2) and doxorubicin/irradiation senescence did not shift the panel.

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