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:
- 金额:$ 22.25万
- 依托单位:
- 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:
- 关键词:Adipose tissueApoptosisAppleBloodCD3 AntigensCDKN2A geneCell AgingCell NucleusCellsClinical TrialsCollagenDataDiffuseDiospyrosDisabled PersonsElderlyEvaluationFatty acid glycerol estersFibrosisFlavanolFlavonolsFunctional disorderGastrocnemius MuscleHandHand StrengthHumanImpairmentInflammationInflammatoryIschemiaLower ExtremityMeasuresMessenger RNAMetabolicMuscleMuscle CellsOutcomePathologyPatientsPerformancePerfusionPeripheral arterial diseasePersonsPhenotypePhysical PerformancePhysiologicalPlacebosPre-Clinical ModelRandomized Clinical TrialsResearch PersonnelSafetySiteSkeletal MuscleStrawberriesT-LymphocyteTestingTissuesWalkingage relatedcardiovascular healthdesigndisabilityfisetinfollow-upfunctional declinefunctional disabilityimmune clearanceimprovednovelparacrinephenotypic biomarkerpilot trialpreclinical studypreventprofibrotic cytokinerandomized trialsarcopeniasecondary outcomesenescencestemstem cellssubcutaneouswalking 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.
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%的衰老细胞分泌炎症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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Mary McGrae McDermott其他文献
159 3D Submillimeter isotropic resolution superficial femoral artery wall MRI using SPACE at 3.0 T
- DOI:
10.1186/1532-429x-10-s1-a60 - 发表时间:
2008-10-22 - 期刊:
- 影响因子:
- 作者:
Zhuoli Zhang;Zhaoyang Fan;YiuCho Chung;Peter Weale;Timothy Carroll;Ioannis Koktzoglou;Renate Jerecic;James Carr;Mary McGrae McDermott;Debiao Li - 通讯作者:
Debiao Li
Changes in study design, gender issues, and other characteristics of clinical research published in three major medical journals from 1971 to 1991
- DOI:
10.1007/bf02599570 - 发表时间:
1995-01-01 - 期刊:
- 影响因子:4.200
- 作者:
Mary McGrae McDermott;Frank Lefevre;Joe Feinglass;Douglas Reifler;Nancy Dolan;Steven Potts;Kathleen Senger - 通讯作者:
Kathleen Senger
Building a research career in general internal medicine
- DOI:
10.1046/j.1525-1497.1998.00028.x - 发表时间:
1998-02-01 - 期刊:
- 影响因子:4.200
- 作者:
Marshall H. Chin;Kenneth E. Covinsky;Mary McGrae McDermott;Eric J. Thomas - 通讯作者:
Eric J. Thomas
Mary McGrae McDermott的其他文献
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{{ item.author }}
{{ truncateString('Mary McGrae McDermott', 18)}}的其他基金
Far Red Light to Improve Functioning in PAD: the LIGHT PAD Trial
远红光改善 PAD 功能:LIGHT PAD 试验
- 批准号:
10572758 - 财政年份:2023
- 资助金额:
$ 22.25万 - 项目类别:
Response to Exercise and Nitric Oxide in PAD: the RESIST PAD Trial
PAD 对运动和一氧化氮的反应:RESIST PAD 试验
- 批准号:
10656845 - 财政年份:2023
- 资助金额:
$ 22.25万 - 项目类别:
ENhancing exercise with LIGHT to improve functioning in PAD: the ENLIGHTEN PAD Trial
利用 LIGHT 加强锻炼以改善 PAD 功能:ENLIGHTEN PAD 试验
- 批准号:
10645929 - 财政年份:2023
- 资助金额:
$ 22.25万 - 项目类别:
BEET root juice to reverse functional impairment in PAD: The BEET PAD Trial
甜菜根汁逆转 PAD 功能损伤:甜菜 PAD 试验
- 批准号:
10440812 - 财政年份:2022
- 资助金额:
$ 22.25万 - 项目类别:
Sequential Multiple Assessment Randomized Trial of Exercise for PAD: SMART Exercise for PAD
PAD 运动的序贯多重评估随机试验:PAD 的 SMART 运动
- 批准号:
10708097 - 财政年份:2022
- 资助金额:
$ 22.25万 - 项目类别:
BEET root juice to reverse functional impairment in PAD: The BEET PAD Trial
甜菜根汁逆转 PAD 功能损伤:甜菜 PAD 试验
- 批准号:
10649671 - 财政年份:2022
- 资助金额:
$ 22.25万 - 项目类别:
Sequential Multiple Assessment Randomized Trial of Exercise for PAD: SMART Exercise for PAD
PAD 运动的序贯多重评估随机试验:PAD 的 SMART 运动
- 批准号:
10584209 - 财政年份:2022
- 资助金额:
$ 22.25万 - 项目类别:
COCOA flavanols to improve walking performance in PAD: the COCOA-PAD II Trial
可可黄烷醇可改善 PAD 的步行表现:COCOA-PAD II 试验
- 批准号:
10430199 - 财政年份:2021
- 资助金额:
$ 22.25万 - 项目类别:
COCOA flavanols to improve walking performance in PAD: the COCOA-PAD II Trial
可可黄烷醇可改善 PAD 的步行表现:COCOA-PAD II 试验
- 批准号:
10685352 - 财政年份:2021
- 资助金额:
$ 22.25万 - 项目类别:
COCOA flavanols to improve walking performance in PAD: the COCOA-PAD II Trial
可可黄烷醇可改善 PAD 的步行表现:COCOA-PAD II 试验
- 批准号:
10209585 - 财政年份:2021
- 资助金额:
$ 22.25万 - 项目类别:
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