# Targeting cellular senescence with oral fisetin supplementation to improve vascular aging

> **NIH NIH F31** · UNIVERSITY OF COLORADO · 2023 · $40,804

## Abstract

PROJECT SUMMARY/ABSTRACT
The purpose of this Ruth L. Kirschstein National Research Service Award is to provide support for Ms.
Sophia Mahoney, a 2nd year PhD student in Dr. Douglas Seals’ (sponsor) laboratory at the University of
Colorado Boulder, to conduct research and training that will prepare her to become an independent
investigator in the field of cardiovascular (CV) aging research aimed at the prevention and treatment of age-
related CV diseases (CVD). As part of her proposed training plan, she aims to both refine research skills
presently under development and learn a variety of new technical, conceptual, and professional skills, including
the use of innovative preclinical mouse models and gaining new experiences using pharmaco-dissection and
proteomic approaches. Her proposed research project seeks to investigate the efficacy of the natural food-
derived senolytic fisetin for preventing arterial dysfunction in old mice and to establish senolysis as the primary
mechanism underlying the beneficial effects. Senescent cells accumulate with aging, and age-related changes
in circulating concentrations of senescence-associated secretory phenotype (SASP) factors have been related
to CVD. However, whether these age-related changes causally impair arterial function is unknown. As such,
decreasing excessive cellular senescence represents a novel therapeutic target for improving arterial
function with aging. Guided by strong preliminary data, Ms. Mahoney will use established preclinical models of
age-related arterial dysfunction and state-of-the-art mechanistic approaches to: Aim 1) directly compare the
effects of fisetin on the arteries (nitric oxide production and reactive oxygen species bioactivity) to the gold
standard experimental approach for clearing senescent cells in vivo (ganciclovir treatment in p16-3MR mice);
Aim 2) determine the mechanistic role of reductions in cellular senescence in mediating the expected
improvements in arterial function in old mice with fisetin treatment; and Aim 3) investigate the role of changes
in circulating factors, with a focus on SASP components, as a key mechanism of fisetin-associated
improvements in arterial function. The expected results will elucidate the role of fisetin-induced senolysis in
improving arterial dysfunction and identify novel SASP factors as new therapeutic targets for treatment of age-
related arterial dysfunction. Overall, the proposed research has the potential to address important NHLBI
Strategic Vision research priorities, including: 1) investigating new pathobiological mechanisms important to
the onset of CVD; and 2) identifying novel therapeutic targets to treat CVD. Dr. Seals is an internationally
recognized and NIH-funded scientist with a strong history of successful mentoring in translational CV research,
particularly in the emerging field of “vascular aging”. Under his supervision and with the guidance of co-
mentors Drs. Zachary Clayton, Judith Campisi, Katelyn Ludwig and Thom...

## Key facts

- **NIH application ID:** 10812313
- **Project number:** 5F31HL165885-02
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Sophia Andrea Mahoney
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $40,804
- **Award type:** 5
- **Project period:** 2022-08-19 → 2025-08-18

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812313

## Citation

> US National Institutes of Health, RePORTER application 10812313, Targeting cellular senescence with oral fisetin supplementation to improve vascular aging (5F31HL165885-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10812313. Licensed CC0.

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