Cells become senescent constantly throughout the body and throughout life, near all as the result of reaching the Hayflick limit on replication, but also due to excessive cell stress, damage, or a toxic environment. A senescent cell ceases replication, enlarges, and secretes a pro-inflammatory, pro-growth mix of signals that attracts the attention of the immune system. In youth senescent cells are efficiently destroyed by the immune system, but this clearance slows down with age. Senescent cells thus accumulate in later life to cause chronic inflammation and disruption to tissue structure and function. The immune system also accumulates senescent cells, and researchers here investigate the epigenetic regulation of gene expression in these cells, with an eye to finding ways to reduce the burden of senescence in these populations.
The age-associated accumulation of senescent cells in tissues is one of the driving causes of aging and age-related disease. Although senescent cells secrete chemokines that facilitate the recruitment of cytotoxic immune cells for their elimination, senescent cells accumulate systemically with advancing age, suggesting that immune cell-mediated elimination of senescent cells becomes impaired with age. Recent evidence highlights a dysfunctional adaptive immune system as a potential cause for the age-associated accumulation in senescent cells. In older humans, both CD4+ and CD8+ T cells acquire features of senescence, which is linked to defective immune responses. However, the gene regulatory mechanisms that promote senescence of CD8+ T cells in aging humans, as well as the contribution of senescent CD8+ T cells to disease, remain poorly understood.
We defined and validated the transcription factor (TF) networks that control the senescence program in CD8+ T cells of a cohort of younger and older donors. One key finding of our study is that the acquisition of senescence is the main driver of epigenomic and gene expression dynamics of CD8+ T cells, with a minor contribution of chronological age. The transition to the senescence state is a major event in the epigenetic life of CD8+ T cells, as it involves the differential expression of 40% of all detectable TFs. Inhibition or downregulation of AP1, KLF5, or RUNX2 modulates the transcriptional output and partially restores the blunted response to stimulation of senescent CD8+ T cells.
