Oxidative stress and aberrant signaling in aging and cognitive decline.
Oxidative stress and aberrant signaling in aging and cognitive decline.
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DOI：
10.1111/j.1474-9726.2007.00294.x
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发表时间：
2007-06
期刊：
影响因子：
7.8
通讯作者：
Schipper, Hyman M
中科院分区：
文献类型：
--
作者：
Droge, Wulf;Schipper, Hyman M
大脑衰老与抗氧化防御和细胞内活性氧 (ROS) 浓度之间的逐渐失衡有关，脂质过氧化、蛋白质氧化和 DNA 氧化产物的增加就是例证。氧化条件不仅会导致结构损伤，还会导致氧化还原敏感信号传导过程（包括胰岛素受体信号传导途径）的设定点发生变化。在缺乏胰岛素的情况下，原本较低的胰岛素受体信号传导会因氧化条件而强烈增强。自噬蛋白水解和沉默调节蛋白活性反过来又被胰岛素信号通路下调，而自噬活性受损与神经退行性疾病有关。在遗传学研究中，胰岛素受体信号传导受损会导致线虫、果蝇和小鼠的寿命显着延长。年龄相关的氧化应激对去乙酰化酶和自噬活性的预测影响以及抗氧化剂的相应影响仍有待实验测试。然而，抗氧化剂已被证明可以改善一些与衰老相关的因素。线粒体 DNA 和电子传递链的氧化损伤、脑内铁和钙稳态的扰动以及血浆半胱氨酸稳态的变化可能共同代表了氧化应激增加的原因和后果。因此，衰老和认知能力下降似乎涉及复杂调节网络内多个节点的变化。
Brain aging is associated with a progressive imbalance between antioxidant defenses and intracellular concentrations of reactive oxygen species (ROS) as exemplified by increases in products of lipid peroxidation, protein oxidation, and DNA oxidation. Oxidative conditions cause not only structural damage but also changes in the set points of redox-sensitive signaling processes including the insulin receptor signaling pathway. In the absence of insulin, the otherwise low insulin receptor signaling is strongly enhanced by oxidative conditions. Autophagic proteolysis and sirtuin activity, in turn, are downregulated by the insulin signaling pathway, and impaired autophagic activity has been associated with neurodegeneration. In genetic studies, impairment of insulin receptor signaling causes spectacular lifespan extension in nematodes, fruit flies, and mice. The predicted effects of age-related oxidative stress on sirtuins and autophagic activity and the corresponding effects of antioxidants remain to be tested experimentally. However, several correlates of aging have been shown to be ameliorated by antioxidants. Oxidative damage to mitochondrial DNA and the electron transport chain, perturbations in brain iron and calcium homeostasis, and changes in plasma cysteine homeostasis may altogether represent causes and consequences of increased oxidative stress. Aging and cognitive decline thus appear to involve changes at multiple nodes within a complex regulatory network.