NFκB nuclear dynamics orchestrate inflammatory aging

Upregulation of nuclear factor κB (NFκB) signaling is a hallmark of aging and a major cause of age-related chronic inflammation. NFκB activity plays a critical role in transcriptional regulation and cell fate determination; however, its physiological function in inflammatory aging remains unclear. Here, we demonstrate that dysfunction of negative feedback regulators of NFκB, IκBα and A20, alters the NFκB nuclear dynamics from oscillatory to sustained, thereby promoting cellular senescence. Sustained NFκB activity by IκBα downregulation enhances inflammatory gene expression through increased NFκB-DNA binding, promotes purine catabolism by downregulating hypoxanthine phosphoribosyltransferase, and arrests the cell cycle. This regulatory mechanism was confirmed in aged mice heart tissues, suggesting that prolonged nuclear localization of NFκB drives chronic inflammation and metabolic rewiring associated with aging.