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

Fisetin减轻PAD患者衰老和运动障碍的初步随机试验 下肢外周动脉疾病（PAD）是老年人残疾的主要原因。在人们 对于PAD，行走活动期间下肢缺血与腓肠肌（即小腿）减少相关 肌纤维大小和腓肠肌纤维化增加。这些腓肠肌异常是 与PAD患者的功能障碍和活动能力丧失相关。然而，很少有治疗方法能改善 PAD患者的残疾。我们假设缺血诱导的衰老细胞在下丘脑中的积累 四肢有助于PAD的行走障碍，非瑟酮，一种黄酮醇和有效的抗衰老疗法， 与安慰剂相比，破坏衰老细胞的药物将改善PAD患者的下肢功能。 衰老细胞是失去正常生理功能的代谢活性细胞。约30- 70%的衰老细胞分泌炎性和促纤维化细胞因子和其他分子。这些 炎性和促纤维化细胞因子和其他分子被称为衰老相关的分泌性细胞因子。 表型（SASP）。SASP局部扩散（旁分泌效应）并全身循环，促进 炎症、干/祖细胞功能障碍和纤维化。衰老细胞抵抗凋亡和免疫 清除，损伤周围组织，并在组织病理部位累积。我们假设 减少衰老细胞将改善PAD患者的行走能力并预防残疾。 非瑟酮是一种黄烷醇，存在于草莓、苹果和柿子中，其破坏衰老细胞（即， 衰老清除疗法）。在临床前研究中确定的三种衰老清除疗法中， 我们的合作研究者柯克兰博士在初步的人体临床试验中评价，非瑟酮具有最好的安全性 profile.因此，我们提出了一个试点随机临床试验，收集初步数据，以检验假设， 非瑟酮将减少血液、脂肪组织和骨骼肌中衰老细胞的丰度，并改善6- 步行34分钟，34人患有PAD。我们的主要目的是评估是否非瑟酮，相比， 安慰剂，改善PAD患者在4个月随访时的6分钟步行距离。次要结局 包括腓肠肌灌注、手握力、短期体能测试（SPPB）和 血液、脂肪组织和腓肠肌中大量具有衰老标记的细胞。探索性 结果包括血液、腓肠肌和脂肪组织中的SASP测量。我们将确定 具有衰老标志物的细胞丰度的更大下降是否与衰老标志物的更大变化有关？ 6分钟步行距离的改善。如果我们的假设是正确的，结果将被用来设计一个确定的 一项随机试验，以确定非瑟酮（一种广泛使用且耐受性良好的疗法）是否能改善行走 残疾人发展计划旨在提高残疾人的生活能力，防止因PAD而致残的大量且不断增加的老年人丧失行动能力。

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.