Department of Physiology, Faculty of Medicine, Complutense University of Madrid (UCM), Madrid, Spain.
Department of Genetics, Physiology and Microbiology, Faculty of Biological Sciences, Complutense University of Madrid (UCM), Jose Antonio Novais s/n, 28040, Madrid, Spain.
Geroscience. 2020 Apr;42(2):653-665. doi: 10.1007/s11357-020-00158-4. Epub 2020 Jan 22.
Damage to DNA is especially important for aging. High DNA repair could contribute, in principle, to lower such damage in long-lived species. However, previous studies showed that repair of endogenous damage to nuclear DNA (base excision repair, BER) is negatively or not correlated with mammalian longevity. However, we hypothesize here that mitochondrial, instead of nuclear, BER is higher in long-lived than in short-lived mammals. We have thus measured activities and/or protein levels of various BER enzymes including DNA glycosylases, NTHL1 and NEIL2, and the APE endonuclease both in total and mitochondrial liver and heart fractions from up to eight mammalian species differing by 13-fold in longevity. Our results show, for the first time, a positive correlation between (mitochondrial) BER and mammalian longevity. This suggests that the low steady-state oxidative damage in mitochondrial DNA of long-lived species would be due to both their lower mitochondrial ROS generation and their higher mitochondrial BER. Long-lived mammals do not need to continuously maintain high nuclear BER levels because they release less mitROS to the cytosol. This can be the reason why they tend to show lower nuclear BER values. The higher mitochondrial BER of long-lived mammals contributes to their superior longevity, agrees with the updated version of the mitochondrial free radical theory of aging, and indicates the special relevance of mitochondria and mitROS for aging.
DNA 损伤对衰老尤为重要。高 DNA 修复在理论上可以降低长寿物种中的这种损伤。然而，先前的研究表明，内源性核 DNA（碱基切除修复，BER）的修复与哺乳动物的长寿呈负相关或不相关。然而，我们在这里假设，线粒体而非核 BER 在长寿哺乳动物中比在短寿哺乳动物中更高。因此，我们测量了来自多达 8 种不同寿命的哺乳动物的肝脏和心脏总提取物和线粒体提取物中各种 BER 酶（包括 DNA 糖苷酶、NTHL1 和 NEIL2 以及 APE 内切酶）的活性和/或蛋白水平，其寿命相差 13 倍。我们的结果首次表明，（线粒体）BER 与哺乳动物的寿命呈正相关。这表明，长寿物种线粒体 DNA 中的低稳态氧化损伤既归因于其较低的线粒体 ROS 生成，也归因于其较高的线粒体 BER。长寿哺乳动物不需要持续维持高水平的核 BER，因为它们向细胞质释放的 mitROS 较少。这可能就是它们倾向于显示较低的核 BER 值的原因。长寿哺乳动物较高的线粒体 BER 有助于它们的优越寿命，符合更新后的线粒体自由基衰老理论，并且表明线粒体和 mitROS 对衰老具有特殊的重要性。
