Schader Tim, Reschke Christina, Spaeth Manuela, Wienstroer Susanne, Wong Szeka, Schröder Katrin
Institute for Cardiovascular Physiology, Goethe-University, 60590 Frankfurt, Germany.
Antioxidants (Basel). 2020 Mar 10;9(3):226. doi: 10.3390/antiox9030226.
According to the free radical theory of aging, reactive oxygen species (ROS) have been proposed to be a major cause of aging for a long time. Meanwhile, it became clear that ROS have diverse functions in a healthy organism. They act as second messengers, and as transient inhibitors of phosphatases and others. In fact, their detrimental role is highly dependent on the context of their production. NADPH oxidases (Nox) have been discovered as a controllable source of ROS. NoxO1 enables constitutive ROS formation by Nox1 by acting as a constitutively active cytosolic subunit of the complex. We previously found that both Nox1 and NoxO1 were highly expressed in the colon, and that NoxO1-/- deficiency reduces colon health. We hypothesized that a healthy colon potentially contributes to longevity and NoxO1 deficiency would reduce lifetime, at least in mouse. In contrast, here we provide evidence that the knockout of NoxO1 results in an elongated life expectancy of mice. No better endothelial function, nor an improved expression of genes related to longevity, such as Sirt1, were found, and therefore may not serve as an explanation for a longer life in NoxO1 deficiency. Rather minor systemic differences, such as lower body weight occur. As a potential reason for longer life, we suggest better DNA repair capacity in NoxO1 deficient mice. Although final fatal DNA damage appears similar between wildtype and NoxO1 knockout animals, we identified less intermediate DNA damage in colon cells of NoxO1-/- mice, while the number of cells with intact DNA is elevated in NoxO1-/- colons. We conclude that NoxO1 deficiency prolongs lifetime of mice, which correlates with less intermediate and potentially fixable DNA damage at least in colon cells.
根据衰老的自由基理论，活性氧（ROS）长期以来被认为是衰老的主要原因。与此同时，人们清楚地认识到ROS在健康机体中具有多种功能。它们作为第二信使，以及作为磷酸酶和其他物质的瞬时抑制剂。事实上，它们的有害作用高度依赖于其产生的背景。NADPH氧化酶（Nox）已被发现是ROS的可控来源。NoxO1作为复合物的组成型活性胞质亚基，使Nox1能够组成型地形成ROS。我们之前发现Nox1和NoxO1在结肠中均高表达，且NoxO1基因敲除会降低结肠健康。我们推测健康的结肠可能有助于延长寿命，而NoxO1缺陷会缩短寿命，至少在小鼠中是这样。相反，在这里我们提供证据表明敲除NoxO1会导致小鼠预期寿命延长。未发现更好的内皮功能，也未发现与长寿相关基因（如Sirt1）的表达改善，因此这些可能无法解释NoxO1缺陷小鼠寿命更长的原因。而是出现了一些较小的全身差异，比如体重降低。作为寿命延长的潜在原因，我们认为NoxO1缺陷小鼠具有更好的DNA修复能力。尽管野生型和NoxO1基因敲除动物最终的致命DNA损伤看起来相似，但我们发现NoxO1基因敲除小鼠结肠细胞中的中间DNA损伤较少，而NoxO1基因敲除的结肠中DNA完整的细胞数量增加。我们得出结论，NoxO1缺陷延长了小鼠的寿命，这至少在结肠细胞中与较少的中间且可能可修复的DNA损伤相关。
