# Thrombogenic susceptibility in middle aged Veterans

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2022 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 10409685
- **Project number:** 5I01CX001932-03
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Sanjana Dayal
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409685

## Citation

> US National Institutes of Health, RePORTER application 10409685, Thrombogenic susceptibility in middle aged Veterans (5I01CX001932-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10409685. Licensed CC0.

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