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 (TEM) and tissue-resident (TRM) 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, TEM cells expressed senescent markers and a GZMK transcriptional signature, while TRM cells maintained site-specific resident phenotypes without exhibiting features of senescence. Both TEM and TRM cells showed age-associated DNA hypomethylation, though TRM 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 TRM cells without immunosenescence.