Conserved epigenetic hallmarks of T cell aging during immunity and malignancy

Tian Mi, Andrew G. Soerens, Shanta Alli, Tae Gun Kang, Anoop Babu Vasandan, Zhaoming Wang, Vaiva Vezys, Shunsuke Kimura, Ilaria Iacobucci, Stephen B. Baylin, Peter A. Jones, Christopher Hiner, April Mueller, Harris Goldstein, Charles G. Mullighan, Caitlin C. Zebley, David Masopust, Ben Youngblood

Research output: Contribution to journalLetterpeer-review

2 Scopus citations

Abstract

Chronological aging correlates with epigenetic modifications at specific loci, calibrated to species lifespan. Such ‘epigenetic clocks’ appear conserved among mammals, but whether they are cell autonomous and restricted by maximal organismal lifespan remains unknown. We used a multilifetime murine model of repeat vaccination and memory T cell transplantation to test whether epigenetic aging tracks with cellular replication and if such clocks continue ‘counting’ beyond species lifespan. Here we found that memory T cell epigenetic clocks tick independently of host age and continue through four lifetimes. Instead of recording chronological time, T cells recorded proliferative experience through modification of cell cycle regulatory genes. Applying this epigenetic profile across a range of human T cell contexts, we found that naive T cells appeared ‘young’ regardless of organism age, while in pediatric patients, T cell acute lymphoblastic leukemia appeared to have epigenetically aged for up to 200 years. Thus, T cell epigenetic clocks measure replicative history and can continue to accumulate well-beyond organismal lifespan.

Original languageEnglish (US)
Pages (from-to)1053-1063
Number of pages11
JournalNature Aging
Volume4
Issue number8
DOIs
StatePublished - Aug 2024

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© The Author(s) 2024.

PubMed: MeSH publication types

  • Journal Article

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