Age-related thymic involution increases vulnerability to cancers and infection in older adults, yet the driving mechanisms and its impact on peripheral T cells remain unclear. Using single-cell sequencing, we here analyzed 387,762 cells from human thymus and peripheral blood of young and aged individuals. Within thymus, we found aging reduced T-lineage potential in early thymic progenitors but increased innate lymphocyte lineage potential. Aged thymus were enriched in mature T cells with low SOX4 expression and inflammatory profiles but depleted of thymic epithelial cells and expression of tissue-restricted antigens. In the periphery, we identified transcriptional features of T cell aging and established a naive T cell-based model for immune age prediction. Furthermore, we identified CD38 as a marker of recent thymic emigrants. Finally, single-cell T cell receptor (TCR) repertoire sequencing identified shifts in TCR repertoire diversity within memory/effector T cells and expanded virus-specific T cells during aging. Collectively, our data offer insights into human thymic involution and peripheral T cell aging and could inform strategies to restore compromised T cell immunity.
© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.