Thrombogenic susceptibility in middle aged Veterans

老年人发病和死亡的主要原因是血栓性并发症，包括 心肌梗死和中风，这些事件是住院的主要原因， 退伍军人健康管理局（VA）系统。然而，血栓形成的机制，由于 老年化在VA患者中研究不足。第二，在中期遇到的风险因素， 生活可能会恶化结果或导致生活中的早期事件。例如，由于肥胖 在美国，糖尿病前期的发病率正在增加，目前的估计表明， 37%的成年人是糖尿病前期。在退伍军人中，四分之一的人患有糖尿病，超过70%的人患有糖尿病。 接受退伍军人管理局护理的退伍军人都很肥胖。同样，糖尿病前期的高发病率也是 在VA患者中很明显。鉴于退伍军人患心血管事件的风险较高， 经常与以前未诊断的糖尿病有关，了解早期年龄相关的 机制在中年退伍军人或没有前驱糖尿病是必要的，以制定预防 未来血管事件的策略。我们已经确定，血栓性增加 中年/老年小鼠的易感性与血小板活化增加有关， 活性氧（ROS）的积累，但其潜在机制尚不清楚。 在初步研究中，我们发现了一个新的观察结果，即沉默调节蛋白3（SIRT 3），一个公认的 与年轻人或小鼠相比，老年人或小鼠血小板中的抗衰老基因显著减少。SIRT3 是一种线粒体脱乙酰酶，精细控制几种电子传递链的活性 (ETC)蛋白质和超氧化物歧化酶2（SOD 2）累积调节ROS水平，但其 在血小板活化中的作用尚不清楚。我们现在已经生成了原理数据证明 这表明SIRT 3的抑制导致血小板活化增加， 减少聚集。因此，我们的中心假设是，在中年退伍军人中， SIRT 3促进血小板中线粒体ROS的积累，导致血小板过度活化 和血栓形成易感性增加，并且这种表型由于存在 肥胖和糖尿病前期。具体目标1将定义SIRT 3在调节中的机制作用 线粒体活性氧水平，血小板活化和血栓形成的易感性增加， 生活老兵具体目标2将研究糖尿病前期是否调节糖尿病的早期发病， SIRT 3介导的线粒体ROS积累、血小板过度活化和恶化 中年退伍军人的血栓易感性。

A primary cause of morbidity and mortality in the elderly is thrombotic complications, including myocardial infarction and stroke, and these events are the leading cause of hospitalization in Veteran Health Administration (VA) system. However, the mechanisms of thrombosis due to aging are understudied in VA patients. Secondly, risk factors that are encountered during mid- life may exacerbate outcome or lead to an early event in life. For example, due to obesity endemic the incidence of pre-diabetes in US is increasing, with current estimates indicating that 37% of adults are pre-diabetic. Amongst Veterans one in four have diabetes, and over 70% of Veterans receiving VA care are obese. Likewise, a high incidence of prediabetes is also apparent in VA patients. Given Veterans are at higher risk for cardiovascular events which are frequently associated with previously undiagnosed diabetes, understanding early age-related mechanisms in mid-life Veterans with or without prediabetes is necessary to develop preventive strategies for future vascular events. We have established that increased thrombotic susceptibility in middle-aged/older mice is associated with increased platelet activation and reactive oxygen species (ROS) accumulation, though the underlying mechanisms are unclear. In pilot studies, we have made the novel observation that sirtuin 3 (SIRT3), a well-established anti-aging gene, is markedly decreased in platelets from aged vs. young human or mice. SIRT3 is a mitochondrial deacetylase that finely controls the activity of several electron transport chain (ETC) proteins and superoxide dismutase 2 (SOD2) to cumulatively regulate ROS levels, but its role in platelet activation is not clear. We have now generated proof of principle data demonstrating that inhibition of SIRT3 leads to increased platelet activation and its activation reduces aggregation. Therefore, our central hypothesis is that, in middle aged Veterans, loss of SIRT3 promotes mitochondrial ROS accumulation in platelets, leading to platelet hyperactivity and increased thrombotic susceptibility, and that this phenotype is accentuated by presence of obesity and pre-diabetes. Specific Aim 1 will define the mechanistic role of SIRT3 in regulation of mitochondrial ROS levels, platelet activation and increased thrombotic susceptibility in mid- life Veterans. Specific Aim 2 will examine whether pre-diabetes modulates early-age onset of SIRT3-mediated mitochondrial ROS accumulation, platelet hyperactivation and exacerbates thrombotic susceptibility in mid-life Veterans.