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Histone modification clocks for robust cross-species biological age prediction and elucidating senescence regulation

ABSTRACT: By analyzing ChIP-seq data across six tissues and six histone marks, we developed 36 tissue-specific histone modification-based epigenetic clocks that detect age acceleration in leukemia and reversal following treatment. Many age-associated loci showed nonlinear trajectories peaking at midlife, and super-enhancer fragmentation was observed with age. Functional validation of an H3K27ac peak near IGF2BP3 confirmed its role in senescence via TRA2A regulation. These clocks also generalized to Drosophila melanogaster, highlighting the evolutionary conservation and utility of histone modifications as aging biomarkers.

ORGANISM(S): Homo sapiens Drosophila melanogaster

PROVIDER: GSE296812 | GEO | 2026/02/24

REPOSITORIES: GEO

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Project description:Epigenetic clocks are a common group of tools used to measure biological aging – the progressive deterioration of cells, tissues and organs. Epigenetic clocks have been trained almost exclusively using blood-based tissues but there is growing interest in estimating epigenetic age using less-invasive oral-based tissues (i.e., buccal or saliva) in both research and commercial settings. However, differentiated cell types across body tissues exhibit unique DNA methylation landscapes and age-related alterations to the DNA methylome. Applying epigenetic clocks derived from blood-based tissues to estimate epigenetic age of oral-based tissues may introduce biases. We tested the within-person comparability of common epigenetic clocks across four tissue types: buccal epithelial, saliva, dry blood spots, and peripheral blood mononuclear cells. We tested 163 distinct tissue samples from 47 individuals aged 19-70 years. Overall, there were significant within-person differences in epigenetic clock estimates from oral-based versus blood-based tissues, with average differences of almost 30 years observed in some age clocks. In addition, most epigenetic clock estimates of blood-based tissues exhibited low correlation with estimates from oral-based tissues despite controlling for cellular proportions and other technical factors. Notably, the Skin and Blood clock exhibited the lowest age acceleration values of any clock across all tissue types, indicating its unique ability to accurately estimate chronological age in both oral- and blood-based tissues. Our findings indicate that application of blood-derived epigenetic clocks in oral-based tissues may not yield comparable estimates of epigenetic age, highlighting the need for careful consideration of tissue type when estimating epigenetic age. NOTE: The full study included children and adult samples, however, the current data only includes the adult samples (sample sizes and age range have been adjusted to reflect the adult data only).

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Histone modification clocks for robust cross-species biological age prediction and elucidating senescence regulation

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