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

非赛汀减少PAD的衰老和活动障碍：首个试验性随机试验 下肢外周动脉疾病(PAD)是老年人残疾的主要原因。在人身上 在PAD中，行走活动中的下肢缺血与腓肠肌(即小腿)减少有关 肌纤维大小和腓肠肌纤维化增加。这些腓肠肌的异常是 与PAD患者的功能损害和行动能力丧失相关。然而，很少有疗法能改善 PAD患者的残疾。我们假设，缺血诱导的衰老细胞在下丘脑 肢体导致PAD和菲赛汀的行走障碍，菲赛汀是一种黄酮醇和有效的抗衰老药物 与安慰剂相比，这可以破坏衰老的细胞，改善PAD中的下肢功能。 衰老细胞是新陈代谢活跃的细胞，失去了正常的生理功能。大约30- 70%的衰老细胞分泌炎性和促纤维化的细胞因子和其他分子。这些 炎性和促纤维化的细胞因子和其他分子被称为衰老相关分泌 表型(SASP)。SASP局部扩散(旁分泌效应)，系统循环，促进 炎症、干细胞/祖细胞功能障碍和纤维化。衰老细胞抵抗细胞凋亡和免疫 清除，破坏周围组织，并在组织病理部位聚集。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、苹果和柿中，可以破坏衰老的细胞(即 裂解疗法)。目前正在进行的临床前研究中确定的三种抗衰老疗法 在与我们的合作者Kirkland博士一起进行的初步人体临床试验中，非瑟丁具有最好的安全性 侧写。因此，我们提出了一项试点随机临床试验，以收集初步数据来检验这一假设 非瑟素可以减少血液、脂肪组织和骨骼肌中衰老细胞的丰度，并改善6- 34例PAD患者的分钟步行距离。我们的主要目标是评估非赛汀是否与 安慰剂，改善PAD患者4个月随访期的6分钟步行距离。次要结果 包括腓肠肌灌注量、握力、短体能电池(SPPB)和 血液、脂肪组织和腓肠肌中有大量带有衰老标记的细胞。探索性的 结果包括血液、腓肠肌和脂肪组织的SASP测量。我们将决定 带有衰老标记的细胞的丰度是否下降得越多，与 改善了6分钟步行距离。如果我们的假设是正确的，结果将被用来设计一个决定性的 一项随机试验，以确定非赛汀，一种广泛使用且耐受性良好的疗法，是否改善步行 它还可以帮助大量且越来越多的老年人因PAD而丧失行动能力，并防止他们丧失行动能力。

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.