Aging is the single greatest risk factor for most chronic diseases, including heart disease. As we age, the risk of heart disease and heart failure rises, driven by factors such as stiff or blocked blood vessels, inflammation, faulty heart valves, irregular heart rhythms, changes in cellular composition, and the heart’s reduced ability to beat rapidly during physical activity or stress. A key hallmark of aging and one component of heart disfunction is mitochondrial damage. Mitochondria, commonly known as our cells’ “power plants,” also play a key role in the way our cells adapt to stress. As we age, our heart mitochondria perform less effectively, leading to changes in the heart’s structure and function. However, the link between these changes in the mitochondria and increased risk for heart disease remains unknown. As a result, there is a lack of proven treatments that target mitochondria to support the aging heart.
Two UW professors are collaborating to study mitochondrial damage in the heart and treatment with the natural supplement urolithin A (UA). The primary investigators are Michael Regnier, professor of Bioengineering, a faculty member in the Institute for Stem Cell and Regenerative Medicine (ISCRM), and the director of the UW Center for Translational Muscle Research (CTMR); and David Marcinek, professor of Radiology and Laboratory Medicine and Pathology, adjunct professor of Bioengineering, co-director of the Nathan Schock Center of Excellence in Basic Biology of Aging at UW, and also a faculty member in ISCRM and CTMR. Regnier and Marcinek have a history of collaborating on projects that examine small molecules. This partnership will advance Regnier’s goal to increase aging muscle research both in the Regnier lab and the CTMR and Marcinek’s goal of connecting fundamental aging research with the outstanding disease focused research at the UW.
“This new project demonstrates the collaborative spirit at the UW and how the resources of multiple UW Centers and Institutes can be leveraged to create exciting new areas of translational research,” Regnier said.
The research is funded by a $3.24 million grant from the National Institute of Aging and will be focused on treatment with UA, a naturally occurring compound that is produced when the gut microbiome metabolizes compounds in foods including berries, walnuts, almonds and pomegranate seeds. Preliminary data indicates that UA improved both how the heart pumped (systolic function) and how it relaxed (diastolic function) in aging mouse hearts. While strong pumping of the heart is essential for supplying blood to the body, relaxation is also key to filling the heart chambers with sufficient blood volume to be pumped. UA has also been shown to boost muscle endurance in both animals and humans as they age.
This new project demonstrates the collaborative spirit at the UW and how the resources of multiple UW Centers and Institutes can be leveraged to create exciting new areas of translational research. Mike Regnier
Building on early results, the team aims to understand how UA improves heart function in older mice. They hypothesize that UA supports heart health by restoring mitochondrial function and deactivating specific aging-related genes. These effects are thought to improve cardiac performance and exercise tolerance by optimizing the heart’s energy use and altering its biomechanics.
“This is an exciting collaboration across the Shock Center, CTMR, and ISCRM because it capitalizes on the unique strengths of each center to unite the biology of aging with heart disease research to improve health as we age,” Marcinek stated.
The study has three goals. The first is to understand how UA improves the aged mitochondria energy production to enhance heart function and exercise capacity. Goal two will examine how UA affects inflammation and communication between different cells in the aging heart. Finally, the researchers will explore whether UA’s effects on the mitochondria lead to better heart muscle contraction.
This is an exciting collaboration across the Shock Center, CTMR, and ISCRM because it capitalizes on the unique strengths of each center to unite the biology of aging with heart disease research to improve health as we age. David Marcinek
The research will provide a deeper understanding of how mitochondrial dysfunction contributes to cardiac aging and how UA and other mitochondrial targeted small molecules might improve heart function in older. As such, the studies could lead to new treatments to support heart health as people age and improve heart function for individuals with cardiac disease and heart failure.