FIsetin to Reduce Senescence and mobility impairmenT in PAD: the FIRST Pilot Randomized Trial

非瑟汀减少PAD患者的衰老和活动障碍：第一项随机试验

FIsetin to Reduce Senescence and mobility impairmenT in PAD: the FIRST Pilot Randomized Trial Lower extremity peripheral artery disease (PAD) is a major cause of disability in older people. In people with PAD, lower extremity ischemia during walking activity is associated with reduced gastrocnemius (i.e. calf) myofiber size and increased gastrocnemius fibrosis. These gastrocnemius muscle abnormalities are associated with functional impairment and mobility loss in people with PAD. Yet few therapies improve disability in people with PAD. We hypothesize that ischemia-induced senescent cell accumulation in the lower extremities contributes to walking impairment in PAD and that fisetin, a flavonol and potent senolytic therapy that destroys senescent cells, will improve lower extremity functioning in PAD, compared to placebo. Senescent cells are metabolically active cells that have lost normal physiologic function. Approximately 30- 70% of senescent cells secrete inflammatory and pro-fibrotic cytokines and other molecules. These inflammatory and pro-fibrotic cytokines and other molecules are called the senescence-associated secretory phenotype (SASP). The SASP diffuses locally (paracrine effect) and circulates systemically, promoting inflammation, stem/progenitor cell dysfunction, and fibrosis. Senescent cells resist apoptosis and immune clearance, damage surrounding tissue, and accumulate at sites of tissue pathology. We hypothesize that reducing senescent cells will improve walking performance and prevent disability in people with PAD. Fisetin is a flavanol, present in strawberries, apples, and persimmons, that destroys senescent cells (i.e. a senolytic therapy). Of three senolytic therapies identified in preclinical studies that are currently undergoing evaluation in preliminary human clinical trials with our co-investigator Dr. Kirkland, fisetin has the best safety profile. Hence, we propose a pilot randomized clinical trial to gather preliminary data to test the hypothesis that fisetin will reduce abundance of senescent cells in blood, adipose tissue, and skeletal muscle, and improve 6- minute walk distance in 34 people with PAD. Our primary aim is to assess whether fisetin, compared to placebo, improves six-minute walk distance at 4-month follow-up in people with PAD. Secondary outcomes include gastrocnemius perfusion, hand grip strength, the short physical performance battery (SPPB), and the abundance of cells with senescent markers in blood, adipose tissue, and gastrocnemius muscle. Exploratory outcomes include SASP measures in blood, gastrocnemius muscle, and adipose tissue. We will determine whether greater declines in abundance of cells with senescent markers are associated with greater improvement in 6-minute walk distance. If our hypotheses are correct, results will be used to design a definitive randomized trial to determine whether fisetin, a widely available and well tolerated therapy, improves walking ability and prevents mobility loss in the large and growing number of older people disabled by PAD.