NRF1-mediated innate immune response drives inflammaging.

Hong Lei, Tian Zhao, Jiaojiao Zhang, Yijia Long, Yongze Chen, Yixuan Zhu, Yuanyuan Meng, Yinmei Tang, Xin Liu, Jiaxing Sun, Zhuoya Li, Jingyi Su, Fengcongzhe Gong, Guo Chen, Baofa Sun, Yanfang Chen, Quan Chen, Yanjun Li, Yushan Zhu

State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Center for Aging and Regeneration, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, China.State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Center for Aging and Regeneration, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, China. · pubmed

Paper

Abstract

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.

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Research summary

NRF1 deficiency mitigates aging phenotypes and extends lifespan in aged mice. The paper addresses the role of NRF1 in innate immune responses and cellular senescence, which are critical factors in the aging process, suggesting potential therapeutic targets for combating the root causes of aging.

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