Fisetin for Improved Vascular Function in Aging

Overseen By Sarah Haydu, MA

Age: 65+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Colorado, Boulder

Must not be taking: Senolytics, Cardiovascular-acting, others

Disqualifiers: Active malignancy, Unstable CVD, others

Compensation: Varies

Number of Visits: 2

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether fisetin, a natural compound in some fruits and vegetables, can improve blood vessel health and reduce artery stiffness in older adults. Researchers aim to determine if fisetin can help by reducing cellular stress and slowing aging processes. The trial will also assess the treatment's safety and ease of adherence for participants. This trial may suit individuals over 65 who are postmenopausal women, have a stable weight, and are not currently facing serious health conditions. Participants will be randomly assigned to receive either fisetin or a placebo. As a Phase 1, Phase 2 trial, this research focuses on understanding how fisetin works in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot participate if you have started new cardiovascular medications within 3 months or certain dietary supplements within 1 month before the trial. If you are taking fisetin or similar compounds, you must stop 6 months before joining.

Is there any evidence suggesting that fisetin treatment is likely to be safe for humans?

Research shows that fisetin, a natural compound in fruits and vegetables, might be safe for use. Studies suggest that fisetin can help manage long-term diseases by targeting old cells that have stopped dividing and can cause inflammation. As a natural substance, fisetin is generally considered safe. Previous research has not reported major side effects in humans, making it a promising area for further study. However, since this trial is in its early stages, more information is needed to confirm these findings. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for improving vascular function in aging?

Unlike the standard treatments for vascular aging, which often focus on managing symptoms or risk factors through medications like statins or antihypertensives, Fisetin is unique because it is a natural compound with potential senolytic properties. Senolytics target senescent cells, which are aged or damaged cells that accumulate over time and contribute to vascular dysfunction. Researchers are excited about Fisetin because it offers a novel approach by potentially removing these harmful cells, thus directly addressing the underlying cause of vascular aging rather than just alleviating symptoms. Additionally, Fisetin is administered intermittently over short periods, which could mean fewer side effects and increased patient compliance compared to daily medications.

What evidence suggests that fisetin might be an effective treatment for improving vascular function in aging?

Research has shown that fisetin, a natural substance in fruits and vegetables, might improve blood vessel health and reduce arterial stiffness in older adults. Animal studies found that fisetin can reduce cellular senescence, a process where cells stop dividing and start causing harm, which is linked to aging and diseases. Fisetin also appears to lower oxidative stress—an imbalance that can damage cells—and inflammation, which, although a response to injury, can be harmful if prolonged. These effects suggest that fisetin could maintain healthier blood vessels and possibly enhance overall blood flow. Participants in this trial will receive either fisetin or a placebo to evaluate these potential benefits. ^{1 2 3 4 6}

Who Is on the Research Team?

Matthew J Rossman, PhD

Principal Investigator

University of Colorado, Boulder

Are You a Good Fit for This Trial?

This trial is for people aged 65 or older, specifically postmenopausal women and men with a BMI under 40. Participants should not have had significant weight changes recently, must be free of serious chronic diseases like unstable heart conditions, and agree to not donate blood during the study.

Inclusion Criteria

I haven't donated blood in the last 8 weeks and won't donate during or for 8 weeks after the study.

I understand and can follow the study's procedures.

I don't have any serious, long-term health problems that are not under control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intermittent treatment with fisetin or placebo, with two, three-day dosing periods separated by two weeks

4 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Fisetin

Trial Overview The trial is testing fisetin, a flavonoid compound thought to improve blood vessel function and reduce stiffness in arteries among older adults. It will compare fisetin's effects against a placebo while exploring how it might work by affecting oxidative stress and other aging-related factors.

How Is the Trial Designed?

Group I: Fisetin Active Control 1 Intervention

Fisetin will be administered in an intermittent manner with two, three-day dosing periods at a dose of 2 mg/kg/day separated by two weeks.

Group II: Placebo Placebo Group 1 Intervention

Placebo capsules identical in appearance to fistin capsules will be administered in an intermittent manner with two, three-day dosing periods separated by two weeks.

Who Is Running the Clinical Trial?

University of Colorado, Boulder

Lead Sponsor

Trials

128

Recruited

29,600+

American Heart Association

Collaborator

Trials

352

Recruited

6,196,000+

Published Research Related to This Trial

In a study involving 42 healthy participants (22 young and 20 elderly), regular intake of cocoa flavanols (CF) for 14 days significantly improved endothelial function, as shown by increased flow-mediated vasodilation in both age groups.

Cocoa flavanol consumption also reduced vascular stiffness and systolic blood pressure in the elderly, suggesting that dietary flavanols can help counteract age-related cardiovascular risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of cocoa flavanol intake on age-dependent vascular stiffness in healthy men: a randomized, controlled, double-masked trial. Heiss, C., Sansone, R., Karimi, H., et al.[2021]

Aging leads to endothelial dysfunction characterized by reduced ability of blood vessels to dilate, which is influenced by an imbalance between relaxing factors like nitric oxide and constricting factors such as thromboxane A2.

Increased oxidative stress significantly contributes to this dysfunction by breaking down nitric oxide, and the impact of these changes varies depending on the species and type of blood vessels involved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Age-related endothelial dysfunction with respect to nitric oxide, endothelium-derived hyperpolarizing factor and cyclooxygenase products. Matz, RL., Schott, C., Stoclet, JC., et al.[2016]

Resveratrol and naringenin, two phenolic compounds, were found to influence potassium (K+) channels in human umbilical vein smooth muscle, suggesting they can affect vascular tone and potentially lead to vasodilation.

The study indicated that the vasodilatory effects of resveratrol are likely mediated through specific K+ channels, while naringenin's effects are primarily associated with 4-AP-sensitive K+ channels, highlighting their distinct mechanisms of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of Potassium Channels in the Vasodilatation Induced by Resveratrol and Naringenin in Isolated Human Umbilical Vein. Protić, D., Radunović, N., Spremović-Rađenović, S., et al.[2019]

Rhus verniciflua Stokes (RVS) heartwood extract has been shown to reduce vasoconstriction in aortic rings, indicating its potential cardiovascular protective effects by promoting better blood circulation.

The active ingredient identified in RVS, fisetin, inhibits calcium signaling pathways in vascular smooth muscle cells, which contributes to its ability to reduce contraction induced by vasoconstrictors like serotonin and phenylephrine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Heartwood extract of Rhus verniciflua Stokes and its active constituent fisetin attenuate vasoconstriction through calcium-dependent mechanism in rat aorta. Park, JM., Lee, JH., Na, CS., et al.[2021]

Aging leads to chronic diseases due to cellular damage and inflammation, with senescent cells contributing to this process through the senescence-associated secretory phenotype (SASP).

Polyphenols found in fruits and vegetables can combat oxidative stress and inflammation, potentially reducing the effects of SASP and lowering the risk of cardiovascular diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protective Role of Polyphenols against Vascular Inflammation, Aging and Cardiovascular Disease. Serino, A., Salazar, G.[2020]

Fisetin, a natural flavonoid, effectively relaxes vascular contractions induced by various agonists in rat aortic rings, indicating its potential as an anti-hypertensive agent.

The relaxation effect of fisetin is linked to its ability to inhibit Rho-kinase activity and reduce phosphorylation of MYPT1 and ERK1/2, suggesting a specific molecular mechanism that operates independently of endothelial nitric oxide synthesis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endothelium-Independent Effect of Fisetin on the Agonist-Induced Regulation of Vascular Contractility. Je, HD., Sohn, UD., La, HO.[2020]

Fisetin, a natural compound, effectively reduces cellular senescence and inflammation in old mice, leading to improved arterial function and increased nitric oxide bioavailability.

The study demonstrated that fisetin lowers arterial stiffness and promotes favorable arterial wall remodeling, suggesting its potential as a therapy for age-related arterial dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence. Mahoney, SA., Venkatasubramanian, R., Darrah, MA., et al.[2023]

Oral supplementation with apigenin significantly improved arterial function in aging mice by restoring endothelial-dependent dilation and increasing nitric oxide bioavailability, demonstrating its potential as a therapeutic for arterial aging.

Apigenin also mitigated age-related aortic stiffness and prevented foam cell formation, indicating its role in reversing key indicators of arterial dysfunction and reducing cardiovascular disease risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apigenin restores endothelial function by ameliorating oxidative stress, reverses aortic stiffening, and mitigates vascular inflammation with aging. Clayton, ZS., Hutton, DA., Brunt, VE., et al.[2022]

In a study involving 15 young and 19 older healthy subjects, flavanol-rich cocoa significantly improved endothelial function, particularly in older individuals, suggesting enhanced vascular responsiveness with age.

The nitric oxide (NO)-dependent mechanism was confirmed as older subjects experienced a notable increase in blood pressure and flow-mediated vasodilation after cocoa consumption, indicating that cocoa may be especially beneficial for cardiovascular health in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aging and vascular responses to flavanol-rich cocoa. Fisher, ND., Hollenberg, NK.[2013]

Fisetin, when administered intravenously or orally to male Sprague-Dawley rats, is rapidly metabolized into sulfates and glucuronides, indicating a quick transformation in the body that may affect its therapeutic efficacy.

The study found that the metabolites of fisetin showed less potency in inhibiting hemolysis compared to the parent compound, suggesting that the bioactive effects of fisetin may be diminished after metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolism and pharmacokinetics of 3,3',4',7-tetrahydroxyflavone (fisetin), 5-hydroxyflavone, and 7-hydroxyflavone and antihemolysis effects of fisetin and its serum metabolites. Shia, CS., Tsai, SY., Kuo, SC., et al.[2022]

Total flavonoids of Flos Chrysanthemi (TFFC) were found to protect endothelial cells from oxidative stress, significantly improving vasorelaxation in rat mesenteric arteries that were impaired by superoxide anions.

TFFC not only induced vasodilation but also countered the negative effects of oxidative stress on calcium influx and membrane potential in endothelial cells, suggesting its potential as a therapeutic agent for cardiovascular diseases linked to oxidative damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total flavonoids of Flos Chrysanthemi protect arterial endothelial cells against oxidative stress. He, D., Ru, X., Wen, L., et al.[2014]

Citations

1. withpower.com withpower.com/trial/phase-2-aging-8-2023-1d19d

Fisetin for Improved Vascular Function in Aging This trial tests if fisetin, a natural substance from fruits and vegetables, can improve blood vessel health and reduce artery stiffness in older adults.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06133634?term=NCT06133634&rank=1

Fisetin to Improve Vascular Function in Older Adults Studies in animal models show that the flavonoid compound fisetin is an effective treatment for reducing cellular senescence and improving vascular function ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3689181/

Fisetin: A Dietary Antioxidant for Health Promotion - PMC It is reported to have neurotrophic, anticarcinogenic, anti-inflammatory, and other health beneficial effects.

4. sciencedirect.com sciencedirect.com/science/article/pii/S0047637424000952

Fisetin as a senotherapeutic agent: Evidence and ... Our review of available data suggests that targeting senescent cells with fisetin offers a promising strategy for managing multiple chronic diseases.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5527824/

Fisetin Acts on Multiple Pathways to Reduce the Impact of Age ... Fisetin can increase brain cell function and survival through maintenance of redox homeostasis, activating neurotrophic factor signaling pathways and ...

6. allclinicaltrials.com allclinicaltrials.com/study/NCT06133634

Fisetin to Improve Vascular Function in Older Adults This is a pilot clinical trial to test the efficacy of intermittent treatment with the flavonoid compound fisetin for improving vascular endothelial function