Asynchronous aging and turnover of human circulating and tissue-resident memory T cells across sites.

Memory T cells are maintained in tissues as circulating effector-memory (T(EM)) and tissue-resident (T(RM)) populations for protective immunity, though the role of site and subset in memory persistence remains undefined. Here, we investigated age-associated dynamics of human T cells in lymphoid organs, mucosal sites, and blood over 10 decades of life using retrospective radiocarbon ((14)C) birth dating, along with cellular, transcriptome, and epigenetic profiling. Memory T cells across peripheral sites exhibited continuous turnover with mean lifespans of 1-2 years, while the spleen contained longer-lived T cells. Over age, T(EM) cells expressed senescent markers and a GZMK transcriptional signature, while T(RM) cells maintained site-specific resident phenotypes without exhibiting features of senescence. Both T(EM) and T(RM) cells showed age-associated DNA hypomethylation, though T(RM) cells exhibited more epigenetically regulated genes. Together, our findings reveal asynchronous aging of human memory T cells by subset and site, as well as persistence of T(RM) cells without immunosenescence.