Functional genomics analysis identifies T and NK cell activation as a driver of epigenetic clock progression

Thomas H. Jonkman, Koen F. Dekkers, Roderick C. Slieker, Crystal D. Grant, M. Arfan Ikram, Marleen M.J. van Greevenbroek, Lude Franke, Jan H. Veldink, Dorret I. Boomsma, P. Eline Slagboom, B. I.O.S. Consortium, Bastiaan T. Heijmans*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Scopus)
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Background: Epigenetic clocks use DNA methylation (DNAm) levels of specific sets of CpG dinucleotides to accurately predict individual chronological age. A popular application of these clocks is to explore whether the deviation of predicted age from chronological age is associated with disease phenotypes, where this deviation is interpreted as a potential biomarker of biological age. This wide application, however, contrasts with the limited insight in the processes that may drive the running of epigenetic clocks. Results: We perform a functional genomics analysis on four epigenetic clocks, including Hannum’s blood predictor and Horvath’s multi-tissue predictor, using blood DNA methylome and transcriptome data from 3132 individuals. The four clocks result in similar predictions of individual chronological age, and their constituting CpGs are correlated in DNAm level and are enriched for similar histone modifications and chromatin states. Interestingly, DNAm levels of CpGs from the clocks are commonly associated with gene expression in trans. The gene sets involved are highly overlapping and enriched for T cell processes. Further analysis of the transcriptome and methylome of sorted blood cell types identifies differences in DNAm between naive and activated T and NK cells as a probable contributor to the clocks. Indeed, within the same donor, the four epigenetic clocks predict naive cells to be up to 40 years younger than activated cells. Conclusions: The ability of epigenetic clocks to predict chronological age involves their ability to detect changes in proportions of naive and activated immune blood cells, an established feature of immuno-senescence. This finding may contribute to the interpretation of associations between clock-derived measures and age-related health outcomes.

Original languageEnglish
Article number24
JournalGenome Biology
Issue number1
Publication statusPublished - 14 Jan 2022

Bibliographical note

Funding Information:
Samples were contributed by LifeLines, the Leiden Longevity Study, The Netherlands Twin Registry (NTR), the Rotterdam Study, the Genetic Research in Isolated Populations program, the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study, and the Prospective ALS study Netherlands (PAN). We thank the participants of all aforementioned biobanks and acknowledge the contributions of the investigators to this study. We also thank Davy Cats and Hailiang Mei from the Sequencing Analysis Support Core (SASC) in the LUMC for their support at various stages of the project, including data pre-processing and maintenance of the Cloud based data analysis infrastructure. This work was carried out on the Dutch national e-infrastructure with the support of SURF Cooperative. The review history is available as Additional file 5. Stephanie McClelland and Anahita Bishop were the editors of this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Funding Information:
This research was financially supported by BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO, numbers 184.021.007 and 184.033.111) and the US National Institutes of Health (RO1AG066887).

Publisher Copyright:
© 2022, The Author(s).


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