Aging is associated with the accumulation of senescent cells and the increase of systemic inflammation. At the cellular level, aneuploidy gradually increases with age, suggesting that centromeric function may be dysregulated during aging, thereby contributing to senescence and inflammaging. Here, we investigated the regulation of centromere integrity in T lymphocytes, which exhibit age-associated aneuploidy and senescent cell accumulation. We have found that resting human lymphocytes from adults harbor a significant population of cells expressing low levels of total CENP-A, while CENP-B and CENP-C levels are not affected. Notably, CENP-A-low cells show lower or non-detectable CENP-A loaded at centromeres, indicating a change in centromere identity. In contrast, T cells from newborns do not exhibit this population.
Furthermore, CENP-A-low T cells are not equally distributed among subsets of adult T cells. This indicates that the CENP-A-low state is associated with age-dependent changes and the functional state of T cells. In vitro, activated T cells in which we have recapitulated this defective centromere structure by genetic knock-out of CENP-A, show a senescent phenotype characterized by the upregulation of p53 target genes and the expression of proinflammatory genes. In addition, CENP-A knock-out T cells display chromosome-specific aneuploidy after proliferation. Overall, our results reveal that centromere structure integrity is impacted through lifespan and determines aneuploidy in T cells, contributing to regulation of senescence and inflammation.
Invited by Suzanne Faure-Dupuy, Alberto De la Iglesia and Hugo Barreto, as part of the Post-doc seminar series.