Thymus Keeps Working Into Old Age — Sex and Smoking Determine How Much

The thymus — the organ responsible for producing mature T cells — has long been assumed to become functionally irrelevant by middle age. This study challenges that assumption, demonstrating that thymic tissue embedded within mediastinal adipose fat can remain active well past age 50, with significant implications for immune competence and healthy aging.

Researchers recruited patients aged 50 and older undergoing cardiothoracic surgery, giving them rare access to mediastinal adipose tissue from multiple chest locations. Using flow cytometry, histology, bulk RNA sequencing, and T cell receptor (TCR) sequencing, they confirmed that functional thymic structures — capable of supporting thymocyte maturation — were present in approximately 48% of patients in superior mediastinal fat and in 35% in inferior mediastinal fat. Thymic-positive samples showed upregulation of genes critical for thymic stromal maintenance (FOXN1, RAG1, RAG2, PSMB11) and downregulation of adipogenesis markers, confirming genuine thymopoietic activity rather than residual anatomical remnants.

To measure thymic output non-invasively, the team validated CD31+CD4+ naive T cells in peripheral blood as recent thymic emigrants (RTEs). RTE percentage correlated strongly with both thymic double-positive T cells and TREC values, providing a reliable blood-based surrogate. Critically, in patients over 50, RTE levels showed no significant decline with chronological age — contrasting sharply with the rapid age-associated decline seen in individuals under 50. Instead, thymic output was highly heterogeneous among older adults, pointing to factors beyond age itself.

Multiple regression analysis identified sex and smoking history as the two strongest independent predictors of residual thymic output in the older cohort. Women had significantly higher RTE frequencies than men, and nonsmokers retained substantially more thymic activity than current or former smokers. BMI, metabolic status, cardiovascular disease, and systemic inflammation showed no significant association with RTE levels. Notably, these sex and smoking differences were absent in patients under 50, suggesting their influence emerges specifically during the later, slower phase of thymic involution.

Higher thymic output was associated with broader TCR repertoire diversity, reduced susceptibility to in-hospital respiratory infections, and lower epigenetic age as measured by DNA methylation clocks. Detailed profiling of naive CD4+ T cell subsets revealed functional and phenotypic heterogeneity shaped by thymic activity. Conversely, tissue inflammation and T cell senescence markers (TEMRA cells) were driven primarily by CMV infection and peripheral environmental exposures rather than thymic function, suggesting these are parallel — not causally linked — aging processes. Together, these findings reframe thymic involution as a modifiable, heterogeneous process influenced by sex and lifestyle factors, with meaningful downstream effects on immune diversity and biological aging.