Department of Biology, University of Rochester, Rochester, NY, USA.
Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China.
Nat Rev Immunol. 2023 Feb;23(2):75-89. doi: 10.1038/s41577-022-00751-y. Epub 2022 Jul 13.
Genomic instability is an important driver of ageing. The accumulation of DNA damage is believed to contribute to ageing by inducing cell death, senescence and tissue dysfunction. However, emerging evidence shows that inflammation is another major consequence of DNA damage. Inflammation is a hallmark of ageing and the driver of multiple age-related diseases. Here, we review the evidence linking DNA damage, inflammation and ageing, highlighting how premature ageing syndromes are associated with inflammation. We discuss the mechanisms by which DNA damage induces inflammation, such as through activation of the cGAS-STING axis and NF-κB activation by ATM. The triggers for activation of these signalling cascades are the age-related accumulation of DNA damage, activation of transposons, cellular senescence and the accumulation of persistent R-loops. We also discuss how epigenetic changes triggered by DNA damage can lead to inflammation and ageing via redistribution of heterochromatin factors. Finally, we discuss potential interventions against age-related inflammation.
基因组不稳定性是衰老的一个重要驱动因素。据信，DNA 损伤的积累通过诱导细胞死亡、衰老和组织功能障碍导致衰老。然而，新出现的证据表明，炎症是 DNA 损伤的另一个主要后果。炎症是衰老的标志，也是多种与年龄相关疾病的驱动因素。在这里，我们回顾了将 DNA 损伤、炎症和衰老联系起来的证据，强调了早衰综合征如何与炎症有关。我们讨论了 DNA 损伤诱导炎症的机制，例如通过 cGAS-STING 轴的激活和 ATM 激活 NF-κB。这些信号级联的激活触发因素是与年龄相关的 DNA 损伤积累、转座子的激活、细胞衰老和持久 R-环的积累。我们还讨论了 DNA 损伤引发的表观遗传变化如何通过异染色质因子的重新分布导致炎症和衰老。最后，我们讨论了针对与年龄相关的炎症的潜在干预措施。
