NRF1-mediated innate immune response drives inflammaging.

Aberrant innate immune responses contribute significantly to cellular senescence, yet the precise interplay between innate immunity and senescence remains poorly characterized. Here, we elucidate the pivotal role of nuclear respiratory factor 1 (NRF1) in orchestrating innate immune responses that drive senescence and the senescence-associated secretory phenotype (SASP). NRF1 deficiency delayed cellular senescence and ameliorated age-related deterioration in multiple organs. Mechanistically, NRF1 enhanced SASP by transcriptionally regulating TBK1 and IRF3, critical nodes in innate immunity essential for senescence induction. Conversely, NRF1 deficiency suppressed innate immune activation, thereby attenuating inflammation associated with senescence and aging. Additionally, DNA damage activated ATM kinase, which phosphorylated NRF1 at Ser393, augmenting the NRF1-TBK1/IRF3-type I interferon axis and exacerbating cellular senescence. Furthermore, NRF1 knockdown treatment effectively mitigated aging phenotypes and extended lifespan in aged mice. Collectively, our findings underscore the essential role of the ATM-NRF1-TBK1/IRF3-type I interferon axis in DNA damage-induced senescence, suggesting that targeted NRF1 modulation holds therapeutic promise for improving inflammaging.