Age- Related Mild Cognitive Impairment and novel protective role of Glutathione: implications for Alzheimer's Disease

尽管老年人认知能力下降的风险增加， 由于阿尔茨海默氏病是一种严重的认知功能障碍（MCI）并进展为阿尔茨海默氏病，其潜在机制尚不清楚， 干预有限。已发表的证据将MCI与增加的氧化应激水平联系起来， 活性氧簇（ROS）。为了防御ROS的破坏性潜力（导致氧化 应激，OxS），细胞通常依赖于抗氧化剂，而谷胱甘肽（GSH）是人体的主要成分。 内源性细胞内抗氧化防御。GSH是由三种氨基酸组成的三肽，半胱氨酸， 甘氨酸和谷氨酸。由于已知老年人患高血压的风险增加， OxS和GSH缺乏，我们调查并报告了老年人细胞内GSH缺乏， 主要是由于细胞内缺乏其前体氨基酸半胱氨酸和甘氨酸，但不是 谷氨酸，并且这些GSH缺乏的老年人具有升高的ROS水平，表明升高的OxS。 补充半胱氨酸（作为n-乙酰半胱氨酸）加甘氨酸口服胶囊2周补充自己的 细胞内浓度，改善细胞内GSH合成，恢复细胞内GSH水平， 降低ROS/OxS到年轻人的水平。GSH也是线粒体膜的关键成分。 抗氧化防御和GSH耗竭诱导线粒体功能障碍，ROS水平升高， 神经元损伤和凋亡。我们研究并报道了衰老过程中线粒体功能障碍和OxS （老年人和老年小鼠）的衰老可以通过纠正GSH缺乏来改善。这些发现 对老年人MCI的影响。在一项正在进行的小型开放标签试点研究中， 补充半胱氨酸和甘氨酸对线粒体功能、OxS和认知功能的安全性和影响 功能（NCT 02348762），我们发现记忆，语言和执行的显着改善 在开始补充半胱氨酸+甘氨酸后的4周、12周和24周， 在停止这些补充剂后12周，益处似乎消退。这些初步数据支持 令人兴奋的可能性是，在老年人中补充半胱氨酸加甘氨酸可以通过以下方式改善MCI： 改善GSH浓度、线粒体功能和/或改善血管/内皮功能，和 降低OxS。这项初步试验的目标是（a）在老年人中建立 MCI、GSH缺乏、受损的线粒体燃料氧化和升高的OxS，和（B）确定 补充半胱氨酸加甘氨酸以纠正这些缺陷是否改善衰老中的MCI的概念。

Although elderly humans have an increased risk of cognitive decline which begins as mild cognitive impairment (MCI) and progresses to Alzheimer's disease, underlying mechanisms are poorly understood, and interventions limited. Published evidence links MCI to elevated oxidative stress caused by increased levels of reactive oxygen species (ROS). To defend against the damaging potential of ROS (which causes oxidative stress, OxS), cells normally depend on antioxidants, and Glutathione (GSH) is the main component of human endogenous intracellular antioxidant defenses. GSH is a tripeptide composed of three amino-acids, cysteine, glycine and glutamic acid. Since elderly humans are known to have an increased risk of developing elevated OxS and GSH deficiency, we investigated and reported that intracellular GSH deficiency in elderly humans occurs primarily due to intracellular deficiency of two of its precursor amino-acids cysteine and glycine, but not glutamic acid, and that these GSH-deficient elderly humans had elevated ROS levels indicating elevated OxS. Supplementing cysteine (as n-acetylcysteine) plus glycine orally as capsules for 2-weeks replenished their own intracellular concentrations, improved intracellular GSH synthesis, restored intracellular GSH levels and lowered ROS/OxS to levels seen in younger humans. GSH is also a key component of mitochondrial antioxidant defenses, and GSH depletion induces mitochondrial dysfunction with elevated ROS levels, neuronal injury and apoptosis. We studied and reported that mitochondrial dysfunction and OxS in aging (elderly humans and aged mice) can be improved by correcting GSH deficiency. These findings have implications for MCI in elderly humans. In a small ongoing open-label pilot study investigating the long-term safety and impact of supplementing cysteine and glycine on mitochondrial function, OxS and cognitive function (NCT02348762), we found significant improvements in memory, language and executive function at 4w, 12w and 24w after starting cysteine plus glycine supplementation, and these benefits appear to recede 12w after stopping these supplements. These preliminary data support the exciting possibility that cysteine plus glycine supplementation in elderly humans could improve MCI by improving GSH concentrations, mitochondrial function, and/or improving vascular/endothelial function, and by lowering OxS. The goals of this pilot trial are to (a) establish the relationship in older humans between MCI, GSH deficiency, impaired mitochondrial fuel oxidation and elevated OxS, and (b) determine proof-of- concept of whether supplementing cysteine plus glycine to correct these defects improves MCI in aging.