NFκB nuclear dynamics orchestrate inflammatory aging

SUMMARY Upregulation of nuclear factor κB (NFκB) signaling is a hallmark of aging and major cause of age-related chronic inflammation; however, its physiological functions and mechanisms remain unclear. By combining mathematical modeling and experiments, we show that dysfunction of negative feedback regulators of NFκB, IκBα and A20, alters the NFκB nuclear dynamics from oscillatory to sustained, promoting cellular senescence by remodeling epigenetic regulation and metabolic landscape. Sustained NFκB activity by IκBα downregulation enhanced inflammation- and senescence-associated gene expression through increased NFκB-DNA binding and slowed the cell cycle by upregulating purine catabolism via mTORC2/AKT pathways. Notably, IκBα knockdown combined with A20 overexpression resulted in lower NFκB amplitude, cytokine expression, and SA-β-gal activity than IκBα knockdown alone. IκBα downregulation is correlated with hypoxanthine phosphoribosyltransferase 1 (HPRT1) expression in the purine salvage pathway in aged mouse hearts. Our study suggests that nuclear NFκB homeostasis is critical for balancing purine metabolism associated with chronic inflammation and tissue aging.