Clinical translation of senolytic therapy with fisetin to improve vascular function in older adults
Description: The majority of cardiovascular diseases (CVD) occur in men and women =65 years of age. Vascular dysfunction, including endothelial dysfunction as assessed by reduced endothelium-dependent dilation (EDD) and aortic stiffening, is a major contributor to increases in CVD risk with age. Declines in bioavailability of the vasodilatory molecule nitric oxide (NO), secondary to reactive oxygen species (ROS)-related oxidative stress, a key source of which is mitochondria (mito), cause vascular aging. Cellular senescence, a state of permanent cell cycle arrest coupled with the secretion of pro-inflammatory factors (i.e., the senescence-associated secretory phenotype [SASP]), is a primary driver of vascular oxidative stress and age-related vascular dysfunction. As such, clinical translation of novel strategies to clear excess senescent cells and improve vascular function in older adults is an urgent biomedical objective. Synthetic pharmaceutical senolytics are unsuitable for healthy aging because of unfavorable safety profiles. The natural compound fisetin is a flavonoid found in foods and available as a dietary supplement. Fisetin reduces senescent cells in vivo when administered intermittently (to clear excess senescent cells, while preserving the base response). I have obtained preclinical data showing that intermittent oral treatment with fisetin decreases arterial senescent cell burden and fully reverses age-related vascular dysfunction in old (26-28 mo) mice. The improvements in vascular function with fisetin are mediated by senolysis, increases in NO bioavailability and suppression of mito-specific oxidative stress. For my AHA Career Development Award research project, I propose a pilot randomized, placebo-controlled, dose-ranging, double-blind clinical trial to assess the safety, tolerability and adherence of intermittent (2x3-day dosing periods, 25 days apart) oral treatment with low (2 mg/kg/day) or high (20 mg/kg/day) dose fisetin vs. placebo. I will also assess the efficacy of fisetin for improving EDD (primary outcome) and reducing aortic stiffness in men and women =65 years (N=60 total, n=20/group). To gain insight into the mechanisms by which fisetin may improve vascular function, I will assess mito oxidative stress-mediated suppression of vascular function, endothelial cell and circulating markers of cellular senescence, and determine how fisetin changes the factors in circulation and how these changes affect endothelial cell function.
Funder: American Heart Association
Amount: $230,000
Funding type: fellowship
Funder scheme: Career Development Award
Start date: 2023-04-01
End date: 2026-03-31
Investigators: Matthew Rossman, Matthew Rossman
Institution: University of Colorado Boulder
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 9
Funder award ID: 23CDA1056582
OpenAlex ID: G1924453078