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

基本信息

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
项目类别：
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

项目摘要

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.

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，步行活动期间的下肢缺血与腓肠肌（即小腿）减少有关肌纤维尺寸和腓肠肌纤维化增加。这些腓肠肌异常是与 PAD 患者的功能障碍和行动能力丧失有关。然而很少有治疗方法能够改善 PAD 患者的残疾。我们假设缺血引起的下丘脑衰老细胞积累四肢会导致 PAD 患者的行走障碍，而非瑟酮（一种黄酮醇和有效的抗衰老疗法）与安慰剂相比，它能破坏衰老细胞，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跃细胞。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。这些炎症和促纤维化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）并全身循环，促进炎症、干/祖细胞功能障碍和纤维化。衰老细胞抵抗细胞凋亡和免疫清除、损伤周围组织并在组织病理部位积聚。我们假设减少衰老细胞将改善外周动脉疾病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，可破坏衰老细胞（即衰老疗法）。目前正在进行的临床前研究中确定的三种 senolytic 疗法中与我们的合作研究员 Kirkland 博士进行初步人体临床试验评估，非瑟丁具有最佳安全性轮廓。因此，我们提出一项试点随机临床试验来收集初步数据来检验以下假设：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- 34 名 PAD 患者的分钟步行距离。我们的主要目的是评估非瑟酮是否与安慰剂在 4 个月的随访中改善了 PAD 患者的六分钟步行距离。次要结果包括腓肠肌灌注、握力、短期体能电池 (SPPB) 和血液、脂肪组织和腓肠肌中含有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记的细胞丰度的大幅下降是否与更大的衰老相关 6 分钟步行距离有所改善。如果我们的假设是正确的，结果将用于设计一个明确的随机试验，以确定非瑟酮（一种广泛使用且耐受性良好的疗法）是否可以改善步行能力并防止大量且不断增加的因 PAD 致残的老年人的行动能力丧失。