Heterogeneity of thymic output in the elderly and its association with sex and smoking.

BACKGROUNDThymic involution with age leads to reduced T cell output and impaired adaptive immunity. However, the extent to which thymic activity persists later in life and how this contributes to immunological aging remains unclear. This study aimed to assess the presence and function of thymic tissue in older adults and identify factors influencing residual thymopoiesis.METHODSPatients aged 50 or older undergoing cardiothoracic surgery were recruited. Thymic structures within mediastinal adipose tissue were evaluated using histology, immunofluorescence, flow cytometry, T cell receptor (TCR) sequencing, and RNA sequencing. Recent thymic emigrants (RTEs) were quantified in peripheral blood and correlated with transcriptomic, epigenetic, and TCR repertoire data. Primary outcomes included thymic tissue identification, RTE frequency, and immune correlates.RESULTSFunctional thymic tissue was identified in mediastinal adipose tissue of older individuals. The frequency of CD31+CD4+ T cells (RTEs) positively correlated with the presence of thymic tissue. Thymic output showed substantial heterogeneity and was influenced by sex and smoking history. Thymic activity was associated with increased TCR repertoire diversity, improved immune protection against infections, and reduced epigenetic aging. Detailed profiling uncovered functional and phenotypic heterogeneity within naive CD4+ T cell subsets shaped by thymic activity.CONCLUSIONThis study demonstrates that thymic function can persist into later life and is modulated by factors such as sex and smoking. These findings suggest that thymic activity during aging is heterogeneous and influenced by more than chronological age alone, with potential implications for immune competence in older adults.