This is a pilot clinical trial to test the efficacy of intermittent treatment with the flavonoid compound fisetin for improving vascular endothelial function and reducing aortic stiffness in older adults. This trial will also determine the potential mechanisms by which fisetin may improve vascular function, including by decreasing mitochondrial oxidative stress, cellular senescence and senescence-associated secretory phenotype (SASP) factors in circulation. Lastly, safety, tolerability and adherence of fisetin treatment will be assessed.

Cellular senescence increases with aging and contributes to physiological dysfunction. Studies in animal models show that the flavonoid compound fisetin is an effective treatment for reducing cellular senescence and improving vascular function with aging. No published studies have used fisetin to target cellular senescence in older adults to improve vascular function. In addition, the biological reasons (mechanisms) by which fistin may improve vascular function in older adults has not been assessed. This study will evaluate if intermittent treatment with fisetin in older adults improves vascular function, reduces biological markers of cellular senescence, oxidative stress and inflammatory factors produced by senescent cells (i.e., senescence-associated secretory phenotype factors). The study will also evaluate safety, tolerability and adherence with fisetin treatment.

Inclusion Criteria:

• Age 65 years or older
• Women must be postmenopausal
• Body mass index (BMI) <40 kg/m2
• Willing to accept random assignment
• Weight stable in the prior 2 months (<2 kg weight change) and willing to remain weight stable throughout the study
• Ability to understand study procedures and to comply with them for the entire length of the study
• No blood donation within 8 weeks prior to baseline testing; willingness to abstain from blood donation during the study and for 8 weeks after study completion
• Absence of established, serious, unstable, chronic clinical disease (e.g., unstable CVD) as determined by study physician of record based on subject medical history, physical examination, resting ECG and standard clinical blood chemistries

Exclusion Criteria:

• Inability to refrain from alcohol for 24 hours prior to outcome assessment
• Individuals taking fisetin, quercetin, luteolin, Dasatinib, piperlongumine or Navitoclax (supplements or drugs with established senolytic effects) within 6 months prior to baseline testing; should new research reveal other dietary supplements or drugs with potential senolytic effects, their use will be evaluated, and their use may lead to exclusion of the subject by the PI
• New use of regular cardiovascular-acting medication which, in the opinion of the PI, affects the outcomes of the study within 3 months prior to starting baseline testing as reported during medication review during screening (these individuals could be enrolled after 3 months of regular use)
• Chronic use of a dietary supplement which, in the opinion of the PI, affects the outcomes of the study, within 1 month prior to starting baseline testing as reported during medication review during screening (these individuals could be enrolled after 1 month of regular use)
• Active malignancy (including myeloma) or malignancy that was active within 5 years prior to baseline testing
• Inability or unwillingness of individual to give written informed consent
• Current or past participation within 3 months in another clinical trial that, in the opinion of the PI, would affect the outcomes of the study
• Known hypersensitivity or allergy to fisetin
• Blood donation within 2 months prior to baseline testing
• Resting blood pressure >160 mmHg systolic or >110 mmHg diastolic
• Regular vigorous aerobic/endurance exercise