Trial of GlyNAC in Older Adults with COVID-19: Glutathione, Inflammation and Recovery

由新型冠状病毒SARS-CoV-2引发的全球大流行导致新冠肺炎，并与很高的 死亡率从3%(美国)到14%(意大利)不等。年龄增加被认为是新冠肺炎的高危人群 由于老年人的高死亡率(OA)。目前尚不清楚为什么新冠肺炎与高死亡率有关，但 来自住院患者的新证据表明，这是一场严重升高的炎症性细胞因子风暴。 细胞因子(尤其是IL-6)是潜在的贡献者。据报道，新冠肺炎患者炎症增加 与外周血淋巴细胞数量呈负相关，并导致免疫功能障碍。我们研究过衰老 20年来，发现纠正内源性抗氧化蛋白谷胱甘肽(GSH)的不足至关重要 对减轻炎症、升高氧化应激(OXS)和受损的线粒体脂肪酸氧化(MFO)很重要 在办公自动化中。GSH是最丰富的内源性、细胞内、抗氧化蛋白，其功能是保护细胞免受毒害。 在线粒体能量产生过程中产生的氧合酶。骨性关节炎患者体内GSH缺乏。我们已经确定并验证了 有效、简单、安全的营养干预称为GlyNAC(GSH前体甘氨酸和NAC-N-N的组合) 乙酰半胱氨酸)来纠正骨性关节炎患者的GSH缺乏症。谷胱甘肽被确定为对抗新冠肺炎的潜在候选者，但 没有与新冠肺炎一起在OA中进行研究。 我们最近完成了一项由美国国立卫生研究院资助的为期16周的OAwith双盲安慰剂对照随机临床试验 在2周和16周时测量结果。补充14天的GlyNAC导致：(1)RBC-GSH-40%；(2) 减轻炎症反应；(3)降低OXS；(4)改善线粒体功能。 在早期对骨性关节炎的初步研究中，我们发现：(1)骨性关节炎存在明显的GSH缺乏、OXS升高和MFO受损； 骨性关节炎患者的谷胱甘肽缺乏是由于其前体氨基酸的可获得性降低导致合成减少所致。 甘氨酸和半胱氨酸，补充GlyNAC 14天可改善[；(3)补充GlyNAC 改善炎症、OXS、MFO、认知和功能。 这些结果与新冠肺炎的骨性关节炎高度相关，因为：(1)新冠肺炎骨性骨性关节炎有很高的死亡风险； 炎症增加与新冠肺炎的高死亡率有关；(3)谷胱甘肽被确定为潜在的候选因素 对抗新冠肺炎；(4)骨关节炎有谷胱甘肽缺乏、慢性炎症和认知障碍，GlyNAC纠正 (5)GlyNAC在我们的试验中具有很强的安全性；(6)GlyNAC、GSH和OXS尚未被研究 在新冠肺炎。(7)GSH可防止流感病毒在啮齿动物体内复制。 基于这些数据，我们提出了一项探索性先导性随机临床试验，以测试补充GlyNAC的效果 与安慰剂在新冠肺炎治疗的骨性关节炎住院14天进行比较，以确定其对临床改善、康复、 生存、认知、功能、炎症、免疫和线粒体功能、谷胱甘肽浓度和氧化应激。 如果成功，这可能确定GlyNAC是一种新的营养补充剂，可以改善COVID患者的健康。

The global pandemic caused by the novel Coronavirus SARS-Cov-2 results in COVID-19 and is associated with a very high mortality rate ranging from 3% (in USA) to 14% (in Italy) Increased age is identified as a high-risk group for COVID-19 due to significantly high mortality in older adults (OA). It is not clear why COVID-19 is associated with high mortality, but emerging evidence from hospitalized patients has identified a `cytokine storm' with severely elevated inflammatory cytokines (especially IL-6) as a potential contributor. Increased inflammation in patients with COVID-19 is reported to correlate negatively with peripheral lymphocyte populations, and contributes to immune dysfunction. We have studied aging for >20 years, and found that correcting the deficiency of the endogenous antioxidant protein glutathione (GSH) is critically important to lower inflammation, elevated oxidative stress (OxS) and impaired mitochondrial fatty-acid oxidation (MFO) in OA. GSH is the most abundant endogenous, intracellular, antioxidant protein and functions by protecting cells from toxic OxS generated during mitochondrial energy production. OA are deficient in GSH. We have identified and validated an effective, simple and safe nutritional intervention called GlyNAC (combination of GSH precursors glycine and NAC-N- acetylcysteine) to correct GSH deficiency in OA. GSH is identified as a potential candidate to combat COVID-19, but has not been studied in OA with COVID-19. We recently completed a 16-week NIH-funded double-blind placebo-controlled randomized clinical trial in OAwith outcomes measured at 2-weeks and 16-weeks. GlyNAC supplementation for 14-days led to: (1) RBC-GSH ­40%; (2) lowered inflammation; (3) lower OxS; (4) improved mitochondrial function. In earlier pilot studies in OA we found that: (1) OA had striking GSH deficiency, elevated OxS and impaired MFO; (2) GSH deficiency in OA occurs due to diminished synthesis, caused by decreased availability of its precursor amino-acids glycine and cysteine, and can be improved by supplementing GlyNAC for 14-days [; (3) GlyNAC supplementation improved inflammation, OxS , MFO, cognition and function. These results are highly relevant to OA with COVID-19 because: (1) OA with COVID-19 have a high mortality risk; (2) increased inflammation is associated with high mortality in COVID-19; (3) GSH is identified as a potential candidate to combat COVID-19; (4) OA have GSH deficiency, chronic inflammation and cognitive impairment and GlyNAC corrects these defects in OA; (5) GlyNAC has a strong safety profile in our trials; (6) GlyNAC, GSH and OxS have not been studied in COVID-19. (7) GSH prevents replication of the influenza virus in rodents. Based on these data, we propose an exploratory pilot randomized clinical trial to test the effect of supplementing GlyNAC vs. placebo for 14-days in hospitalized in OA with COVID-19 to determine the impact on clinical improvement, recovery, survival, cognition, function, inflammation, immune and mitochondrial function, GSH concentrations and oxidative stress. If successful, this could identify GlyNAC as a novel nutritional supplement to improve the health of patients with COVID.