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

70 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests if fisetin, a natural substance from fruits and vegetables, can improve blood vessel health and reduce artery stiffness in older adults. It works by making old cells act younger, reducing cell stress, and lowering inflammation. The study will also check if fisetin is safe and well-tolerated. Fisetin is a natural flavonoid found in various fruits and vegetables, known for its antioxidant, anti-inflammatory, and anti-carcinogenic properties.

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.

What data supports the effectiveness of the drug Fisetin for improving vascular function in aging?

Research shows that Fisetin can improve arterial function in old mice by reducing cell aging and inflammation, which helps increase the availability of nitric oxide (a molecule that helps blood vessels relax). This suggests Fisetin might help improve blood vessel health as we age. ^{1 2 3 4 5}

Is fisetin safe for human use?

Fisetin, a natural compound found in fruits and vegetables, has been studied in animals and shows potential benefits for vascular health, but specific safety data in humans is limited. Animal studies suggest it may help improve blood circulation and reduce age-related arterial issues, but more research is needed to confirm its safety in humans. ^{1 6 7 8 9}

How does the drug fisetin differ from other treatments for improving vascular function in aging?

Fisetin is unique because it acts as a senolytic, meaning it helps remove old, dysfunctional cells that contribute to aging-related issues in blood vessels. This process reduces inflammation and oxidative stress, improving the function of the cells lining the blood vessels and decreasing arterial stiffness, which is not a common mechanism in other treatments for vascular aging. ^{1 2 5 10 11}

Research Team

Matthew J Rossman, PhD

Principal Investigator

University of Colorado, Boulder

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Apigenin restores endothelial function by ameliorating oxidative stress, reverses aortic stiffening, and mitigates vascular inflammation with aging. [2022]

3. Ireland pubmed.ncbi.nlm.nih.gov

Total flavonoids of Flos Chrysanthemi protect arterial endothelial cells against oxidative stress. [2014]

4. Switzerland pubmed.ncbi.nlm.nih.gov

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

5. Netherlands pubmed.ncbi.nlm.nih.gov

Impact of cocoa flavanol intake on age-dependent vascular stiffness in healthy men: a randomized, controlled, double-masked trial. [2021]

6. Korea (South) pubmed.ncbi.nlm.nih.gov

Endothelium-Independent Effect of Fisetin on the Agonist-Induced Regulation of Vascular Contractility. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

The Role of Potassium Channels in the Vasodilatation Induced by Resveratrol and Naringenin in Isolated Human Umbilical Vein. [2019]

8. United States 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. [2022]

9. England 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. [2021]

10. Czech Republic pubmed.ncbi.nlm.nih.gov

Age-related endothelial dysfunction with respect to nitric oxide, endothelium-derived hyperpolarizing factor and cyclooxygenase products. [2016]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Aging and vascular responses to flavanol-rich cocoa. [2013]