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.
Veterans are at increased risk for heart attack and stroke as they age. These conditions occur due to blood clots in the blood vessels and are a primary cause of morbidity/mortality in the elderly veterans. Risk factors such as obesity induced diabetes encountered during mid-life may increase the disease burden. Therefore, this proposal will study early mechanisms in mid-life Veterans for enhanced blood clot formation in presence or absence of pre-diabetes.
