Chen Jian-Hua, Hales C Nicholes, Ozanne Susan E
Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QR, UK.
Nucleic Acids Res. 2007;35(22):7417-28. doi: 10.1093/nar/gkm681. Epub 2007 Oct 2.
Cellular senescence has long been used as a cellular model for understanding mechanisms underlying the ageing process. Compelling evidence obtained in recent years demonstrate that DNA damage is a common mediator for both replicative senescence, which is triggered by telomere shortening, and premature cellular senescence induced by various stressors such as oncogenic stress and oxidative stress. Extensive observations suggest that DNA damage accumulates with age and that this may be due to an increase in production of reactive oxygen species (ROS) and a decline in DNA repair capacity with age. Mutation or disrupted expression of genes that increase DNA damage often result in premature ageing. In contrast, interventions that enhance resistance to oxidative stress and attenuate DNA damage contribute towards longevity. This evidence suggests that genomic instability plays a causative role in the ageing process. However, conflicting findings exist which indicate that ROS production and oxidative damage levels of macromolecules including DNA do not always correlate with lifespan in model animals. Here we review the recent advances in addressing the role of DNA damage in cellular senescence and organismal ageing.
长期以来，细胞衰老一直被用作一种细胞模型，以了解衰老过程背后的机制。近年来获得的有力证据表明，DNA损伤是复制性衰老（由端粒缩短引发）和由各种应激源（如致癌应激和氧化应激）诱导的细胞早衰的共同介导因素。大量观察结果表明，DNA损伤会随着年龄的增长而积累，这可能是由于活性氧（ROS）生成增加以及随着年龄增长DNA修复能力下降所致。增加DNA损伤的基因突变或基因表达紊乱通常会导致早衰。相反，增强对氧化应激的抵抗力并减轻DNA损伤的干预措施有助于延长寿命。这一证据表明基因组不稳定在衰老过程中起因果作用。然而，也存在相互矛盾的研究结果，这些结果表明包括DNA在内的大分子的ROS生成和氧化损伤水平并不总是与模式动物的寿命相关。在此，我们综述了在探讨DNA损伤在细胞衰老和机体衰老中的作用方面的最新进展。
