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 (¹⁴C) 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.