The Ageing Biology Centre, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.
The Ageing Biology Centre, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.
Mech Ageing Dev. 2018 Mar;170:30-36. doi: 10.1016/j.mad.2017.08.005. Epub 2017 Aug 25.
Cell senescence is an important driver of the ageing process. The accumulation of senescent cells in tissues is accelerated by stress signals from senescent cells that induce DNA damage and ultimately senescence in bystander cells. We examine here the interplay of senescence-associated mitochondrial dysfunction (SAMD)-driven production of reactive oxygen species (ROS) and senescence-associated secretory phenotype (SASP) in causing the bystander effect. We show that in various modes of fibroblast senescence ROS are necessary and sufficient to activate the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which facilitates a large part of the SASP. This ROS-NF-κB axis causes the DNA damage response in bystander cells. Cytokines IL-6 and IL-8 are major components of the pro-inflammatory SASP in senescent fibroblasts. However, their activation in senescence is only partially controlled by NF-κB, and they are thus not strong candidates as intercellular mediators of the bystander effect as mediated by the ROS-NF-κB axis.
细胞衰老（Cell senescence）是衰老过程的重要驱动因素。衰老细胞产生的应激信号会加速组织中衰老细胞的积累，从而诱导旁观者细胞中的 DNA 损伤并最终导致衰老。我们在此研究了与衰老相关的线粒体功能障碍（SAMD）驱动的活性氧（ROS）产生与衰老相关的分泌表型（SASP）在引起旁观者效应中的相互作用。我们表明，在各种成纤维细胞衰老模式中，ROS 是激活转录因子核因子κB 轻链增强子的激活 B 细胞（NF-κB）所必需且充分的，这促进了 SASP 的很大一部分。这个 ROS-NF-κB 轴导致旁观者细胞中的 DNA 损伤反应。细胞因子白细胞介素-6（IL-6）和白细胞介素-8（IL-8）是衰老成纤维细胞中促炎 SASP 的主要成分。然而，它们在衰老中的激活仅部分受 NF-κB 控制，因此它们不是 ROS-NF-κB 轴介导的旁观者效应的强有力的细胞间介质候选物。
