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Peer-reviewedCC BY 4.0PLOS One

Characterization of DNA methylation in PBMCs and donor-matched iPSCs shows age-related methylation is reset during stem cell reprogramming

  • Xylena Reed1
  • Cory A. Weller2
  • Sara Saez-Atienzar3
  • Alexandra Beilina4
  • Sultana Solaiman5
  • Makayla Portley6
  • Mary Kaileh7
  • Roshni Roy8
  • Jinhui Ding9
  • A. Zenobia Moore
  • D. Thad Whitaker
  • Bryan J. Traynor
4 more authors
  • Luigi Ferrucci
  • J. Raphael Gibbs
  • Sonja W. Scholz
  • Mark R. Cookson
9 affiliations
  1. 1Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America
  2. 2Center for Alzheimer’s and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America
  3. 3DataTecnica LLC, Washington, District of Columbia, United States of America
  4. 4Neuromuscular Disease Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America
  5. 5Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, United States of America
  6. 6Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
  7. 7Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America
  8. 8Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
  9. 9Department of Neurology, Johns Hopkins University Medical Center, Baltimore, Maryland, United States of America
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Abstract

DNA methylation is an important epigenetic mechanism that helps define and maintain cellular functions. It is influenced by many factors, including environmental exposures, genotype, cell type, sex, and aging. Since age is the primary risk factor for developing neurodegenerative diseases, it is important to determine if age-related DNA methylation is retained when cells are reprogrammed to an induced Pluripotent Stem Cell (iPSC) state. Here, we selected peripheral blood mononuclear cells (PBMCs; n = 99) from a cohort of diverse and healthy individuals enrolled in the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (GESTALT) study to reprogram to iPSCs. After reprogramming, the resulting iPSCs were evaluated for DNA methylation signatures to determine if they reflect the confounding factors of aging and environmental effects. Data from genome-wide DNA methylation arrays in both cell types showed that age-related methylation measured by epigenetic clocks is largely reset to an early methylation age after reprogramming of PBMCs to iPSCs. We further examined the epigenetic age of each cell type using an Epigenome-wide Association Study (EWAS) and identified a set of methylation Quantitative Trait Loci in each cell type. Our results show that age-related DNA methylation is largely reset in iPSCs, and each cell type has a unique set of methylation sites that are modified by population-level genetic variation.

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Cite

BibTeXRIS
BibTeX
@article{reed2026characterization,
  title = {{Characterization of DNA methylation in PBMCs and donor-matched iPSCs shows age-related methylation is reset during stem cell reprogramming}},
  author = {Xylena Reed and Cory A. Weller and Sara Saez-Atienzar and Alexandra Beilina and Sultana Solaiman and Makayla Portley and Mary Kaileh and Roshni Roy and Jinhui Ding and A. Zenobia Moore and D. Thad Whitaker and Bryan J. Traynor and Luigi Ferrucci and J. Raphael Gibbs and Sonja W. Scholz and Mark R. Cookson},
  journal = {PLOS One},
  year = {2026},
  month = sep,
  doi = {10.1371/journal.pone.0356501},
  url = {https://doi.org/10.1371/journal.pone.0356501},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Characterization of DNA methylation in PBMCs and donor-matched iPSCs shows age-related methylation is reset during stem cell reprogramming
AU  - Xylena Reed
AU  - Cory A. Weller
AU  - Sara Saez-Atienzar
AU  - Alexandra Beilina
AU  - Sultana Solaiman
AU  - Makayla Portley
AU  - Mary Kaileh
AU  - Roshni Roy
AU  - Jinhui Ding
AU  - A. Zenobia Moore
AU  - D. Thad Whitaker
AU  - Bryan J. Traynor
AU  - Luigi Ferrucci
AU  - J. Raphael Gibbs
AU  - Sonja W. Scholz
AU  - Mark R. Cookson
PY  - 2026
DA  - 2026/09/08
JO  - PLOS One
DO  - 10.1371/journal.pone.0356501
UR  - https://doi.org/10.1371/journal.pone.0356501
AB  - DNA methylation is an important epigenetic mechanism that helps define and maintain cellular functions. It is influenced by many factors, including environmental exposures, genotype, cell type, sex, and aging. Since age is the primary risk factor for developing neurodegenerative diseases, it is important to determine if age-related DNA methylation is retained when cells are reprogrammed to an induced Pluripotent Stem Cell (iPSC) state. Here, we selected peripheral blood mononuclear cells (PBMCs; n = 99) from a cohort of diverse and healthy individuals enrolled in the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (GESTALT) study to reprogram to iPSCs. After reprogramming, the resulting iPSCs were evaluated for DNA methylation signatures to determine if they reflect the confounding factors of aging and environmental effects. Data from genome-wide DNA methylation arrays in both cell types showed that age-related methylation measured by epigenetic clocks is largely reset to an early methylation age after reprogramming of PBMCs to iPSCs. We further examined the epigenetic age of each cell type using an Epigenome-wide Association Study (EWAS) and identified a set of methylation Quantitative Trait Loci in each cell type. Our results show that age-related DNA methylation is largely reset in iPSCs, and each cell type has a unique set of methylation sites that are modified by population-level genetic variation.
SN  - 1932-6203
ER  -