Conserved epigenetic hallmarks of T-cell aging during immunity and malignancy

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 multi-lifetime 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. 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 naïve T cells appeared ‘young’ regardless of organism age, while in pediatric patients, T-cell acute lymphoblastic leukemia (T-ALL) 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. 2 replicates of endogenous T cell samples, 3 replicates of half lifetime samples, 5 replicates of 2 lifetime samples, 3 replicates of 4 lifetime samples, 2 replicates of Naive T cells from aged mice, 2 replicates of TCM from aged mice, 2 replicates of TEM from aged mice