Graduation Date

5-2022

Document Type

Master's Thesis

Degree

Master of Science

Program

Biological Science

Program Director

Meredith Protas, PhD

First Reader

Simon Melov, PhD

Second Reader

Judith Campisi, PhD

Abstract

Cardiovascular disease is the leading cause of death in the United States. Cardiac function declines with age, and promotes a number of age-related disorders, including atrial fibrillation and heart failure. Mitochondrial oxidative stress has long been suspected as a primary driver of aging pathology in multiple tissues, including the heart and brain. We used several phenotypic assays to characterize chemically-induced accelerated cardiac aging, as well as two transgenic knockout models for heart and brain specific loss of superoxide dismutase (SOD2), a mitochondrial antioxidant protein.

We first accelerated aging in mice by treating with doxorubicin (DOXO), a chemotherapeutic drug. One group of DOXO-treated mice were also given a compound that kills senescent cells (termed a “senolytic”). We found that the senolytic 25HC does not significantly rescue cardiac function in 12-month-old, DOXO-treated, p16-3MR mice. However, 25HC treatment helped normalize metabolic function in DOXO-treated mice compared to vehicle-treated mice. 25HC also improved survival in DOXO-treated mice.

In a second model of induced aging, transgenic mice were subjected to mitochondrial oxidative stress in the heart and brain following tissue-specific knockout of Sod2. We determined functional outcomes using echocardiography, metabolic analysis, and behavioral analysis. Sod2 loss caused deficits in cardiac function of mice when knockout was directed to cardiomyocytes, resulting in a novel cardiomyopathy model. Sod2 loss also caused decline in motor function in mice when knockout was directed to dopaminergic neurons, resulting in a novel Parkinson’s Disease model.

We also investigated a novel imaging technique that used contrast agents and micro CT. This technique relies on perfusing a radio-opaque substance into the subject to visualize the vasculature via x-rays in vivo, thus allowing visualization of the aging heart and vasculature, as well as other organ systems with associated vascular networks.

Available for download on Friday, May 30, 2025

Share

COinS