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

Thymic involution is an age-related process that results in reduced T cell production and impaired adaptive immunity. However, it remains uncertain the extent of thymic activity later in life and how this contributes to immunological ageing. Here, we identified thymic tissue within mediastinal adipose locations in aged individuals and confirmed its functional capacity through multi-omics analysis. Percentage of CD31+ CD4+ T cells correlated positively with thymic tissue presence. Thymic output in elderly showed a high degree of heterogeneity was modulated by gender and smoking history. Thymus activity was associated with a diverse TCR repertoire, unique transcriptomic profile, and distinct epigenetic signature. Adipose tissue inflammation was found to be independent of thymic activity but associated with the presence of circulating T cells with an immunosenescent phenotype. Further analysis revealed functional and phenotypic heterogeneity within distinct naïve CD4 T cell subsets, which are influenced by thymic activity. To investigate if natural involution of the thymus in old age associates with increased risk of mortality, we investigated whole blood derived DNA methylation (DNAm) for a correlation between DNAm GrimAge clock age acceleration and recent thymic emigrants (RTEs). Blood derived DNAm changes previously associated with smoking were also specifically analaysed to explore any association between smoking and thymic output.