NFκB dynamics‐dependent epigenetic changes modulate inflammatory gene expression and induce cellular senescence

Upregulation of nuclear factor κB (NFκB) signaling is a hallmark of aging and a major cause of age‐related chronic inflammation. However, its effect on cellular senescence remains unclear. Here, we show that alteration of NFκB nuclear dynamics from oscillatory to sustained by depleting a negative feedback regulator of NFκB pathway, NFκB inhibitor alpha (IκBα), in the presence of tumor necrosis factor α (TNFα) promotes cellular senescence. Sustained NFκB activity enhanced inflammatory gene expression through increased NFκB‐DNA binding and slowed the cell cycle. IκBα protein was decreased under replicative or oxidative stress in vitro . Furthermore, a decrease in IκBα protein and an increase in DNA‐NFκB binding at the transcription start sites of age‐associated genes in aged mouse hearts suggested that nuclear NFκB dynamics may play a critical role in the progression of aging. Our study suggests that nuclear NFκB dynamics‐dependent epigenetic changes regulated over time in a living system, possibly through a decrease in IκBα, enhance the expression of inflammatory genes to advance the cells to a senescent state.