# Role of cellular senescence in cardiovascular aging

> **NIH NIH R01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2021 · $177,483

## Abstract

PROJECT SUMMARY/ABSTRACT
Aging is the primary risk factor for cardiovascular diseases (CVD). Increased CVD risk with aging is mediated
primarily by arterial dysfunction, including impaired vascular endothelial and increased large elastic
artery (e.g., aorta) stiffening. These changes in vascular function are largely due to excess reactive oxygen
species (ROS), which reduces the bioavailability of the vasodilatory molecule nitric oxide (NO) and induces
structural changes in arteries. However, the upstream events regulating these processes are incompletely
understood. A mechanism thought to underly age-related arterial dysfunction is cellular senescence, a largely
permanent cell cycle arrest which leads to the secretion of pro-inflammatory molecules, collectively referred to
as the senescence-associated secretory phenotype (SASP). Indeed, cellular senescence contributes to
vascular aging and therefore represents a novel therapeutic target for reducing the risk of CVD with aging.
We have shown that genetic- and pharmacological-based senescent cell clearance (senolysis) in aged animals
improves arterial function; however, the translational potential of senolytic therapies studied to data is hindered
by their toxicity to non-senescent cells and/or unfavorable safety profiles. Therefore, it is biomedically
relevant to develop novel and safe senolytics. Natural, food-derived compounds represent highly promising
approaches to accomplish this goal. Fisetin is a flavonoid with proposed senolytic properties found in a variety
of commonly consumed foods such as cucumbers and strawberries. Due to the content variations in food,
fisetin-rich diets are not feasible; however, fisetin is available as a dietary supplement with a favorable safety
profile in humans. Moreover, short-term (1-2 months), high dose fisetin administration in an intermittent
manner is emerging as a promising, non-pharmacological, senotherapeutic strategy. As such, fisetin is an
excellent candidate for clinical translation.
The purpose of this administrative supplement, through the NIH Office of Dietary Supplements, is to
determine the efficacy of the food-derived senolytic fisetin for treating age-related arterial dysfunction in old
mice and to establish senolysis as the primary mechanism underlying the beneficial effects. This study
represents a critical step for the eventual clinical translation of this dietary supplement to humans.
Hypothesis 1: Oral supplementation with fisetin will improve arterial function in old mice. The improvements
will be similar to those observed with in vivo genetic clearance of senescent cells.
Hypothesis 2: Improvements in arterial function with fisetin will be driven by reductions in cellular senescence.
Hypothesis 3: Fisetin-associated alterations in the circulating milieu/the SASP will improve endothelial cell
function and these effects will be mediated via reductions in cellular senescence.

## Key facts

- **NIH application ID:** 10393209
- **Project number:** 3R01AG055822-04S1
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Simon Melov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $177,483
- **Award type:** 3
- **Project period:** 2018-06-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10393209

## Citation

> US National Institutes of Health, RePORTER application 10393209, Role of cellular senescence in cardiovascular aging (3R01AG055822-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10393209. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*