Aging diminishes thymic output, reduces naive T cells, promotes memory T-cell accumulation, and impairs thymic regeneration.

Aging increases susceptibility to a wide range of diseases, partially due to alterations in T lymphocytes. This study aimed to characterize age-related changes in T-cell output, phenotype, and function under basal conditions and after myocardial infarction (MI). Compared with young mice (2-6 mo), aged mice (≥18 mo) demonstrated reduced thymic size and fewer developing thymocytes. Accordingly, circulating T-cell counts were significantly lower in aged mice than in young mice. Interestingly, the spleen and bone marrow of aged mice showed increased T-cell accumulation, primarily due to expansion of memory T cells. Similarly, older humans (≥60 yr old) exhibited reduced circulating T cells and a higher proportion of memory T cells. Under basal conditions, aged splenic T cells expressed higher mRNA levels of proinflammatory and cytotoxic factors (e.g., <i>Ifnγ</i>, <i>Tnfα</i>, <i>granzyme b</i>, and <i>perforin</i>). Moreover, aged T cells exhibited a higher frequency of PD-1⁺, TIGIT⁺, LAG-3⁺, and CTLA-4⁺ cells compared with young T cells, indicative of an exhausted phenotype. Metabolically, aged T cells showed higher basal glycolytic and mitochondrial oxidative phosphorylation. Following MI, thymic regeneration was evident in young mice by <i>day 14</i>, whereas the aged thymus remained atrophic. In addition, aged MI mice exhibited reduced naïve T cells and increased memory T cells in the spleen and bone marrow compared with young mice. In conclusion, our study reveals that aging diminishes thymocyte output and circulating T-cell pools, facilitates memory T-cell accumulation, and compromises thymic regeneration under basal conditions and post-MI.<b>NEW & NOTEWORTHY</b> This study reveals that aging causes thymic involution and reduces thymic output and circulating T cells. Interestingly, aging promotes memory T-cell accumulation in the spleen and bone marrow. Aged T cells exhibit an exhausted phenotype with increased metabolic activity. Following myocardial infarction (MI), aged mice display impaired thymic regeneration, decreased naïve T cells, and increased memory T cells. Collectively, these findings characterize age-related changes in T cells under basal conditions and after MI.