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  • The Independent Epigenetic Clock of T Cells

    T cells exhibit a unique ability to proliferate indefinitely without experiencing the functional decline typical of most cell types. Researchers at St. Jude Children’s Research Hospital and the University of Minnesota have uncovered the distinct 'epigenetic clock' of T-cell aging, revealing that T cells can outlive their host organism by at least four lifetimes. Their findings, published in Nature Aging, also indicate that the age of healthy T cells is not directly linked to the organism's chronological age, and malignant T cells from pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL) can appear to be up to 200 years old.

    Investigating Cellular Aging Through Epigenetic Markers
    The researchers explored the aging process of cells by examining specific biomarkers known as epigenetic markers. These markers, including genetic mutations, telomere shortening, and methylation patterns, accumulate over time and provide a detailed retrospective of a cell’s life cycle, independent of the organism itself. “The immune system by nature must mount a rapid proliferative response to a pathogen or a tumor,” said Ben Youngblood, PhD, co-corresponding author from the St. Jude Department of Immunology. “And in some settings, such as endemic pathogens or chronic viral infections, this happens over and over again. That's a lot of proliferation that these T cells undergo in the lifespan of a human.”

    A Model to Test T-Cell Longevity
    In collaboration with co-corresponding author David Masopust, PhD, from the University of Minnesota, the researchers utilized a model that tracked the same line of T cells through several mouse life cycles. This model helped address whether the epigenetic clocks of T cells are constrained by the lifespan of the organism. “Dr. Masopust started this model assuming the cells would eventually decline, but they didn't, they just kept going,” Youngblood explained. “This led to his foundational 10-year mouse study which we subsequently used to address whether organismal lifespan limits constrain epigenetic clocks.”

    Using the model and an epigenetic clock developed specifically for T cells, the researchers investigated the DNA methylation patterns of T-cell lineages. They discovered that the epigenetic clock continued to count beyond the organism’s lifespan, indicating that T cells are not limited by the host’s life expectancy. “Is there an end to an epigenetic clock? Does it plateau? And it didn't for up to four lifetimes, it just kept counting, which was incredible,” said Youngblood. “These cells are not bound by the reasonable limits of organism lifespan.”

    Malignant T Cells and Accelerated Aging
    The researchers also studied the epigenetic clocks of T cells under conditions of rapid and prolonged proliferation, such as in pediatric T-ALL. They found that the T cells of T-ALL patients appeared to be much older than expected based on the patients' chronological age. “If epigenetic clocks were linked to the host’s chronologic age, then you would expect the T cells from pediatric T-ALL patients to appear young in age,” said co-corresponding author Caitlin Zebley, MD, PhD, from the St. Jude Department of Bone Marrow Transplantation & Cellular Therapy. “But our clock predicted these cells to be very old.”

    From an experiential perspective, the T cells of T-ALL patients seemed to range from 100 to 200 years old. “We think this was related to the fact that they were proliferating so rapidly,” Zebley concluded. This T-ALL model provided valuable insights into the aging process of leukemia cells. “We were able to use this as a subtraction model from all other programs in leukemia to identify ones that are associated with normal aging and proliferation versus ones that are distinct to leukemia,” Youngblood said. “We gained a better idea of which epigenetic programs are associated with leukemia and which are just normal hyperproliferation and aging.”

    Implications for Future Research
    The survival of T cells is critical to our immune system’s function and overall survival. “T-cells have so many opportunities to turn cancerous,” Youngblood noted, “But they can't, otherwise humanity wouldn't exist.” The team’s ongoing research aims to further understand the mechanisms preventing T cells from undergoing malignant transformation, and these efforts hold the potential for developing therapies to halt or reverse age-related impairments in the future.

    Publication Details
    Mi, T., Soerens, A.G., Alli, S. et al. Conserved epigenetic hallmarks of T cell aging during immunity and malignancy. Nat Aging (2024). https://doi.org/10.1038/s43587-024-00649-5

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