Jurk Diana, Wilson Caroline, Passos João F, Oakley Fiona, Correia-Melo Clara, Greaves Laura, Saretzki Gabriele, Fox Chris, Lawless Conor, Anderson Rhys, Hewitt Graeme, Pender Sylvia Lf, Fullard Nicola, Nelson Glyn, Mann Jelena, van de Sluis Bart, Mann Derek A, von Zglinicki Thomas
Institute for Ageing and Health, Newcastle University, NE4 5PL, UK.
Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Nat Commun. 2014 Jun 24;2:4172. doi: 10.1038/ncomms5172.
Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-κB induces premature ageing in mice. We also show that these mice have reduced regeneration in liver and gut. nfkb1(-/-) fibroblasts exhibit aggravated cell senescence because of an enhanced autocrine and paracrine feedback through NF-κB, COX-2 and ROS, which stabilizes DNA damage. Preferential accumulation of telomere-dysfunctional senescent cells in nfkb1(-/-) tissues is blocked by anti-inflammatory or antioxidant treatment of mice, and this rescues tissue regenerative potential. Frequencies of senescent cells in liver and intestinal crypts quantitatively predict mean and maximum lifespan in both short- and long-lived mice cohorts. These data indicate that systemic chronic inflammation can accelerate ageing via ROS-mediated exacerbation of telomere dysfunction and cell senescence in the absence of any other genetic or environmental factor.
慢性炎症与正常衰老和病理性衰老相关。在此我们表明，转录因子NF-κB的nfkb1亚基敲除所诱导的慢性、进行性低度炎症会导致小鼠早衰。我们还表明，这些小鼠的肝脏和肠道再生能力下降。nfkb1(-/-)成纤维细胞由于通过NF-κB、COX-2和ROS增强的自分泌和旁分泌反馈而表现出加剧的细胞衰老，这会稳定DNA损伤。对小鼠进行抗炎或抗氧化治疗可阻止nfkb1(-/-)组织中端粒功能异常衰老细胞的优先积累，从而挽救组织再生潜力。在短期和长期存活的小鼠群体中，肝脏和肠隐窝中衰老细胞的频率可定量预测平均寿命和最大寿命。这些数据表明，在没有任何其他遗传或环境因素的情况下，全身性慢性炎症可通过ROS介导的端粒功能障碍和细胞衰老加剧来加速衰老。
