The investigators propose a pilot randomized trial to gather preliminary data to test the hypothesis that Fisetin will reduce abundance of senescent cells in blood, skeletal muscle, and both subcutaneous and inter muscular adipose tissue and improve 6-minute walk distance in 34 people with peripheral artery disease (PAD). the investigators will determine whether greater declines in abundance of cells with senescent markers are associated with greater improvement in 6-minute walk distance in people with peripheral artery disease. In exploratory analyses, the investigators will assess whether Fisetin reduces interleukin-6 (IL-6) and novel senescent markers in adipose tissue, muscle, and/or blood.
An ankle brachial index (ABI) less than or equal to 0.90 at baseline.
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 angiographic evidence of PAD defined as at least 70% stenosis of an artery supplying the lower extremities.
An ABI of greater than 0.90 and less than or equal to 1.00 who experience a 20% or greater drop in ABI in either leg after the heel-rise test will also be included.
Above- or below-knee amputation
Critical limb ischemia defined as an ABI less than 0.40 with signs or symptoms of critical limb ischemia
Wheelchair confinement or requiring a walker to ambulate
Walking is limited by a symptom other than PAD
Parallel
Fisetin
DrugFisetin is a flavanol, present in strawberries, apples, and persimmons, that destroys senescent cells (i.e. a senolytic therapy). Of three senolytic therapies being tested in clinical trials, fisetin has the best safety profile.
Placebo
DrugThe placebo will be matched to the Fisetin intervention
Six-minute Walk Distance
Among older people with PAD, the investigators will determine whether, compared to placebo, fisetin improves six-minute walk distance at 4-month follow-up
Hand Grip Strength
Among older people with PAD, the investigators will determine whether, compared to placebo, fisetin improves hand grip strength at 4-month follow-up. readouts.
Short physical performance battery (SPPB)
Among older people with PAD, the investigators will determine whether, compared to placebo, fisetin improves the short physical performance battery (SPPB) at 4-month follow-up. SPPB range, range 0-12, 12-best
Number of cells with senescence markers
Among older people with PAD, the investigators will determine whether, compared to placebo, fisetin decreases cells with senescence markers in lower extremity adipose tissue, blood (CD3+ T lymphocytes), and gastrocnemius muscle at 4-month follow-up.
Gastrocnemius perfusion
Among older people with PAD, the investigators will determine whether, compared to placebo, fisetin improves gastrocnemius perfusion at 4-month follow-up. The investigators will use arterial spin labeling with magnetic resonance imaging (MRI) and post-cuff occlusion hyperemia to measure changes in calf perfusion at 3 Tesla. MRI perfusion will be measured using cuff occlusion hyperemia while the participant is supine. Gastrocnemius perfusion will be measured in ml/minute per 100g of tissue.
Abundance of oxylipin dihomo-15d-PGJ2
Among older people with PAD, the investigators will determine whether, compared to placebo, fisetin changes abundance of oxylipin dihomo-15d-PGJ2 in blood at 4-month follow-up.
Abundance of interleukin-6 markers
Among older people with PAD, the investigators will determine whether, compared to placebo, fisetin changes abundance of interleukin-6 (IL-6) markers in blood at 4-month follow-up. Quantitative reverse transcription-PCR (qRT-PCR) will be performed by Dr. Peterson's lab for RNA encoding IL-6 markers in adipose tissue, including interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), IL-1α, growth differentiation factor 15, and IL-6. Abundance of IL-6 markers will be measured in units of pg/mL.
Gastrocnemius muscle fibrosis
Among older people with PAD, the investigators will determine whether reduced senescent cell abundance and whether reduced IL-6 factor abundance in blood, gastrocnemius muscle, and adipose tissue, respectively, are correlated with reduced gastrocnemius muscle fibrosis at 4-month follow up. Antibodies to collagen I and III will quantify extracellular matrix composition. Picrosirius Red histochemistry will quantify total fibrous collagen, with polarized light to assess collagen organization.
Gastrocnemius muscle collagen
Among older people with PAD, the investigators will determine whether reduced senescent cell abundance and whether reduced IL-6 factor abundance in blood, gastrocnemius muscle, and adipose tissue, respectively, are correlated with reduced gastrocnemius muscle collagen at 4-month follow up. Antibodies to collagen I and III will quantify extracellular matrix composition. Picrosirius Red histochemistry will quantify total fibrous collagen, with polarized light to assess collagen organization.
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