Thrombogenic susceptibility in middle aged Veterans

老年人发病率和死亡率的主要原因是血栓并发症，包括 心肌梗死和中风，这些事件是#年住院的主要原因 退伍军人健康管理局(VA)系统。然而，由于血栓形成的机制 VA患者的衰老研究还不够深入。其次，年中遇到的风险因素 生活可能会加剧结果，或导致人生早期的事件。例如，由于肥胖 糖尿病前期在美国的发病率正在上升，目前的估计表明 37%的成年人是糖尿病前期。在退伍军人中，四分之一患有糖尿病，超过70%的人 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。鉴于退伍军人发生心血管事件的风险更高， 经常与以前未诊断的糖尿病有关，了解早期年龄相关 有或没有糖尿病前期的中年退伍军人的机制对于制定预防措施是必要的 针对未来血管事件的策略。我们已经证实，血栓形成增加 中年/老年小鼠的易感性与血小板活化和 活性氧(ROS)的积累，尽管潜在的机制尚不清楚。 在初步研究中，我们做了一个新的观察到，sirtuin 3(SIRT3)，一个公认的 与年轻人或小鼠相比，抗衰老基因在老年人的血小板中显著减少。SIRT3 是一种线粒体脱乙酰酶，可以精细地控制几个电子传输链的活性 (ETC)蛋白质和超氧化物歧化酶2(SOD2)累积调节ROS水平，但其 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的证明 证明抑制SIRT3导致血小板活化及其活化增加 减少聚合。因此，我们的中心假设是，在中年退伍军人中， SIRT3促进线粒体ROS在血小板内积聚，导致血小板过度活动 并增加血栓易感性，而且这种表型因存在 肥胖和糖尿病前期。具体目标1将定义SIRT3在监管中的机械作用 线粒体ROS水平、血小板活化和血栓易感性增加的中期 退伍军人。特定目标2将检查糖尿病前期是否调节早期发病 SIRT3介导的线粒体ROS积聚、血小板过度激活和加重 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.