Senescent cell accumulation is associated with T-cell imbalance in the skin

Organismal aging is accompanied by the accumulation of senescent cells - damaged, non-functional cells that exhibit cell cycle arrest, resistance to apoptosis, metabolic dysfunction, and production of a wide range of pro-inflammatory substances. The age-related accumulation of these cells is associated with impaired tissue function, contributes to chronic inflammation (inflammaging), and promotes the development of various age-associated diseases. Conversely, the elimination of senescent cells restores tissue functions and positively affects overall metabolism. Under normal conditions, senescent cells are removed by the innate immune system; however, the efficiency of this process declines with age. The involvement of adaptive immunity and the role of T cells in the clearance of senescent cells remain poorly understood. The aim of this study was to identify alterations in local T cell immunity associated with the accumulation of senescent cells in human skin. The analysis was performed on publicly available single-cell RNA-sequencing data from skin biopsies, and the senescent status was assessed using the SenePy algorithm with Gaussian mixture models. It was found that the emergence of senescent cells occurs heterogeneously across cell types within the tissue. The accumulation of these cells is associated with alterations in the CD4+ to CD8+ T cell ratio, as well as with an increased abundance of regulatory T cells. Functional analysis revealed that these quantitative age-related shifts were accompanied by more pronounced activation of regulatory T cells together with features of anergy and exhaustion in CD8+ T cells, whereas functional changes in CD4+ T cells were heterogeneous. These findings underscore the importance of adaptive immunity in maintaining tissue homeostasis and suggest potential age-related dysfunction of tissue-resident T cells. Understanding the mechanisms underlying the interaction between adaptive immunity and senescent cells is crucial for the development of senolytic vaccines and other immunological approaches aimed at enhancing endogenous elimination of senescent cells.