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

非瑟酮可减少 PAD 中的衰老和活动障碍：第一个试点随机试验

• 批准号: 10526851
• 负责人: Mary McGrae McDermott
• 金额: $ 22.25万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10526851
• 关键词: Adipose tissue; Apoptosis; Apple; Blood; CD3 Antigens; CDKN2A gene; Cell Aging; Cell Nucleus; Cells; Clinical Trials; Collagen; Data; Diffuse; Diospyros; Disabled Persons; Elderly; Evaluation; Fatty acid glycerol esters; Fibrosis; Flavanol; Flavonols; Functional disorder; Gastrocnemius Muscle; Hand; Hand Strength; Human; Impairment; Inflammation; Inflammatory; Ischemia; Lower Extremity; Measures; Messenger RNA; Metabolic; Muscle; Muscle Cells; Outcome; Pathology; Patients; Performance; Perfusion; Peripheral arterial disease; Persons; Phenotype; Physical Performance; Physiological; Placebos; Pre-Clinical Model; Randomized Clinical Trials; Research Personnel; Safety; Site; Skeletal Muscle; Strawberries; T-Lymphocyte; Testing; Tissues; Walking; age related; cardiovascular health; design; disability; fisetin; follow-up; functional decline; functional disability; immune clearance; improved; novel; paracrine; phenotypic biomarker; pilot trial; preclinical study; prevent; profibrotic cytokine; randomized trial; sarcopenia; secondary outcome; senescence; stem; stem cells; subcutaneous; walking speed

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.

减少PAD中衰老和迁移障碍的Fisetin：第一个试验随机试验 下肢外围动脉疾病（PAD）是老年人残疾的主要原因。在人中 使用PAD，步行活动期间的下肢缺血与胃癌减少有关（即小腿） 肌纤维大小和胃纤维纤维化的增加。这些腹腔肌肉异常是 与PAD患者的功能障碍和流动性损失相关。然而疗法很少有所改善 患有垫子的人的残疾。我们假设缺血诱导的衰老细胞在较低的 四肢有助于步行障碍，而菲瑟蛋白，黄酮醇和有效的鼻溶治疗 与安慰剂相比，这会破坏衰老细胞，可以改善垫子的下肢功能。 衰老细胞是代谢活性细胞，失去了正常的生理功能。大约30- 70％的衰老细胞分泌炎症和促纤维化细胞因子和其他分子。这些 炎症和促纤维性细胞因子和其他分子称为衰老相关分泌 表型（SASP）。 SASP在本地扩散（旁分泌效应）并系统地循环，促进 炎症，茎/祖细胞功能障碍和纤维化。衰老细胞抵抗凋亡和免疫 清除，组织周围的损害，并在组织病理的部位积聚。我们假设这一点 减少衰老细胞将改善步行性能并防止PAD患者的残疾。 Fisetin是一种黄酮醇，存在于草莓，苹果和柿子中，会破坏衰老细胞（即 塞溶治疗）。在临床前研究中确定的三种塞溶性疗法中 与我们的共同投资者Kirkland博士进行初步人类临床试验评估，Fisetin具有最佳的安全性 轮廓。因此，我们提出了一项飞行员随机临床试验，以收集初步数据，以检验以下假设。 fisetin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-- 34人带垫的人步行距离。我们的主要目的是评估Fisetin是否与 安慰剂，在患有垫子的人的4个月后续步行距离六分钟的步行路程中。次要结果 包括胃癌灌注，手握力，短体性能电池（SPPB）和 血液，脂肪组织和胃肌肉肌肉中具有衰老标记物的细胞丰度。探索性 结局包括血液，胃肌肌肉和脂肪组织的SASP测量。我们将确定 具有衰老标记物的细胞丰富的细胞是否较大与较大的细胞下降有关 步行6分钟步行路程的改善。如果我们的假设正确，结果将用于设计确定的 随机试验以确定菲塞丁（一种广泛可用且耐受性良好的疗法）是否可以改善步行 能力并防止大量且越来越多的老年人通过PAD残疾人的流动性损失。