Fisetin to Reduce Senescence and Mobility Impairment in PAD

Inclusion Criteria:

First, all participants will be age 50 and older. Second, all participants will have PAD. PAD will be defined as:

1. An ankle brachial index (ABI) less than or equal to 0.90 at baseline.

2. Vascular lab evidence of PAD (such as a toe brachial pressure less than or equal to 0.70 or an ankle brachial index less than or equal to 0.90), or angiographicevidence of PAD defined as at least 70% stenosis of an artery supplying the lowerextremities.

3. An ABI of greater than 0.90 and less than or equal to 1.00 who experience a 20% orgreater drop in ABI in either leg after the heel-rise test will also be included.

Exclusion Criteria:

1. Above- or below-knee amputation

2. Critical limb ischemia defined as an ABI less than 0.40 with signs or symptoms ofcritical limb ischemia

3. Wheelchair confinement or requiring a walker to ambulate

4. Walking is limited by a symptom other than PAD

5. Current foot ulcer on bottom of foot

6. Failure to successfully complete the study run-in

7. Planned major surgery, coronary or leg revascularization during the next five months

8. Major surgery, coronary or leg revascularization or major cardiovascular event inthe previous three months

9. Major medical illness including lung disease requiring oxygen, Parkinson's disease,a life-threatening illness with life expectancy less than six months, or cancerrequiring treatment in the previous two years. [NOTE: potential participants maystill qualify if they have had treatment for an early stage cancer in the past twoyears and the prognosis is excellent. Participants who require oxygen only at nightmay still qualify.]

10. Mini-Mental Status Examination (MMSE) score less than 23

11. Allergy to fisetin

12. Currently taking fisetin or has taken fisetin in previous three months

13. Non-English speaking

14. Current participation in or completion of a clinical trial intervention in theprevious three months. [NOTE: after completing a stem cell or gene therapyintervention, participants will become eligible after the final study follow-upvisit of the stem cell or gene therapy study so long as at least six months havepassed since the final intervention administration. After completing a clinicaltrial (other than stem cell or gene therapy), participants will be eligible afterthe final study intervention as long as at least three months have passed since thefinal intervention of the trial.]

15. Visual impairment that limits walking ability.

16. Six-minute walk distance of less than 500 feet or greater than1600 feet.

17. Participation in a supervised treadmill exercise program in previous three months.

18. Participants may be excluded if they are unwilling to undergo a fat biopsy. However,if investigators find recruitment significantly slows due to this exclusion,participants may still be able to participate in the trial if they refuse the fatbiopsy.

19. Women who are not menopausal will be excluded. Menopause is defined as absence of amenstrual period in the past 12 months.

20. People with a bilirubin above 2.2 mg/dl, with serum aspartate transaminase (AST) oralanine aminotransferase (ALT) more than four times the upper limit of normal.

21. Hemoglobin less than 7.0 g/dl, white blood count less than 2,000/mm3, white bloodcount greater than 20,000/mm3, platelet count less than 40,000/uL.

22. Estimated glomerular filtration rate (eGFR) less than 25 ml/min/1.73 m2

23. HemoglobinA1C great than 10 as a marker of poor diabetes control.

24. People who are Human Immunodeficiency Virus positive (HIV+) and people with activehepatitis B or active hepatitis C infections who do not have a low viral load.

25. People taking warfarin and other sensitive substrates of CYP2C9, CYP2C19, or CYP1A2that have a narrow therapeutic window will be excluded, unless the drug can be heldfor at least two days prior to the first day of each study drug administration andcan continue to be held for ten hours after the second dose of study drugadministration for each of the two days of study drug dosing.

26. Body mass index (BMI) great than 43.

27. In addition to the above criteria, investigator discretion will be used to determineif the trial is unsafe or not a good fit for the potential participant. In someinstances, patients whose medications or laboratory data meet exclusion criteria mayparticipate at the Principal Investigator's discretion.