Wednesday, February 5, 2025
2/5/2025
Summary Thrombotic events such as myocardial infarction, stroke and deep vein thrombosis are the leading causes of morbidity and mortality in the elderly. The objective of this proposal is to test the usefulness of a calorie-restriction (CR) intervention to diminish prothrombotic effects in aged mice or aged mice with type 2 diabetes and identify a druggable target. Our pioneering studies have established that increased thrombotic susceptibility in aging is associated with platelet hyperactivity due to excessive accumulation of oxidants or the reactive oxygen species. We also observed that the loss in mitochondrial superoxide-dismutase (SOD2) activity within platelets increases mitochondrial-oxidant burden in aged mice and enhances platelet activation and susceptibility to arterial thrombosis. Our novel pilot data shows that sirtuin 3 (SIRT3), a mitochondrial-deacetylase that regulates the activity of several mitochondrial-proteins including SOD2 is markedly decreased in platelets from aged mice and humans. Consistent with these observations, in an ongoing clinical study, we observed that increased platelet activation in healthy older humans and obese-diabetics was overcome by pre-incubation with SIRT3 activator or a SOD2 mimetic, suggesting a Mito-oxidant dependent mechanisms. Recently, we also reported that the increased potential for venous thrombosis during aging is mediated via increased total cell-free DNA and this increase is likely due to elevation in mitochondrial DNA. The damaged circulating mitochondria with cardiolipin surface may also enhance thrombin generation potential and venous thrombosis. So, a major goal of this proposal is to determine a role of damaged-mitochondria that mediates age-associated arterial and venous thrombosis and identify preventive measures. In search for a mitochondria-based protective mechanisms, we conducted a pilot study and employed a 30% CR in aged mice or aged mice with type 2 diabetes for a month. This 30% CR increased platelet-SIRT3, decreased damage in mitochondria, decreased platelet activation and lowered thrombotic susceptibility. We hypothesize that CR protects from age-associated arterial- and venous thrombosis through distinct mitochondrial mechanisms. We will also test that the presence of insulin resistance or type two diabetes exacerbates mitochondrial damage and enhances thrombosis which is also preventable with CR. Aim 1 will focus on platelet SIRT3 activation as a protective mechanism of CR for arterial thrombosis. Aim 2 will test whether CR prevents from circulating damaged- mitochondria and mitochondrial-DNA and lowers the susceptibility to venous thrombosis. Thus, the significance of this proposal is in establishing usefulness of a healthy life-style-intervention to diminish prothrombotic effects in aging and age-associated comorbidity and identify a druggable target downstream to CR for translational application.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).