Senolytics to Improve Cognition and Mobility in Older Adults at Risk of Alzheimer’s Disease
Senolytics 可改善有阿尔茨海默病风险的老年人的认知和活动能力
基本信息
- 批准号:10287509
- 负责人:
- 金额:$ 20万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-15 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:Activities of Daily LivingAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAmericanBiologicalBiological MarkersBloodBlood VesselsBlood flowBostonBrainBrain regionCapsicumCellsCerebrovascular CirculationChronic DiseaseClinicCocoa PowderCognitionCognitiveCognitive deficitsConsumptionDasatinibDataDevelopmentDiseaseDoseElderlyEtiologyFlavanolFutureGaitGait speedGeroscienceGoalsHumanImpaired cognitionImpairmentInterruptionInterventionJointsLeadMeasuresMusNeurofibrillary TanglesOutcomePhenotypePhysical PerformancePilot ProjectsPlantsProcessQuercetinRandomized Controlled TrialsRegimenRegulationResearchResearch PersonnelResourcesRestRiskRodentSerumTestingTherapeutic AgentsTissuesTrail Making TestTyrosine Kinase InhibitorUrineVentricularWorkage relatedagedarmbasecognitive disabilitycognitive functioncognitive performancecognitive taskdensityexecutive functionexercise capacityexperiencefallsfrailtyfrontal lobefunctional disabilityhealthspanhuman dataidiopathic pulmonary fibrosisimprovedmiddle cerebral arterymild cognitive impairmentneural circuitneuron lossneurovascular couplingnovel strategiesopen labelpreventrandomized controlled designrecruitresponsesenescencetau phosphorylationvascular risk factor
项目摘要
Abstract/Project Summary
Abnormalities in cognition and mobility are common accompaniments of aging that often precede the
development of Alzheimer’s disease. Among their many etiologies, these abnormalities are associated with
alterations in the regulation of cerebral blood flow to frontal regions of the brain that subserve executive
functions and gait speed. We have previously shown that treatment with cocoa flavanols can improve blood
flow in response to a cognitive task (neurovascular coupling [NVC]), as well as executive function in older
people with impaired NVC. These compounds can also reduce the number of senescent cells and their toxic
secretory products (SASP) in a variety of tissues. In mice, “senolytic” compounds such as flavanols and
tyrosine kinase inhibitors, have been shown to reduce neurofibrillary tangle density, neuron loss, and
ventricular enlargement, and in humans with idiopathic pulmonary fibrosis, improve gait speed and other
functional abilities. Based on these findings, we hypothesize that the flavanol, Quercetin, and tyrosine kinase
inhibitor, Dasatinib, (Q+D) will improve NVC in response to an executive task, reduce circulating SASP
components, and in so doing, improve cognition and mobility in older adults who are at risk of Alzheimer’s
disease. Our specific aims are: 1) To conduct a 12-week single arm, open label, pre-post pilot study to
determine the feasibility and recruitment challenges of studying intermittent doses of Quercetin and Dasatinib
(Q+D) in 12 older adults aged 70 to 90 years with slow gait speed (<1.0 m/sec) and Mild Cognitive Impairment;
2) To obtain preliminary data on the effect of this Q+D regimen on: a) resting cerebral blood flow (CBF) and
neurovascular coupling (NVC) during an executive task, b) gait speed and executive function, and c) other
secondary measures of physical and cognitive performance; and 3) To develop preliminary evidence
concerning whether Q+D is associated with a) a reduction in biomarkers of senescence in serum and urine
and senescent cells in blood, and b) whether reductions in these biomarkers are associated with improvements
in NVC, gait speed, and executive function. This research will leverage the expertise and resources of the
Boston Pepper Center and Mayo Clinic-based Translational Geroscience Network. Its results may identify a
novel approach for improving cerebral blood flow regulation, mobility, and cognition in older adults, and
preventing their progression to Alzheimer’s disease. The study may also help establish proof-of-concept that
the cognitive and functional disabilities of older age may arise, in part, from the secretory products of
senescent cells and be alleviated by senolytic agents.
摘要/项目摘要
认知能力和活动能力的下降是衰老的常见表现,
阿尔茨海默病的发展。在其众多病因中,这些异常与
大脑额叶区的脑血流量调节的改变,
功能和步态速度。我们以前已经证明,可可黄烷醇治疗可以改善血液
对认知任务的反应(神经血管耦合[NVC])以及老年人的执行功能
NVC受损的人这些化合物还可以减少衰老细胞的数量及其毒性。
多种组织中的分泌产物(SASP)。在小鼠中,“衰老清除”化合物如黄烷醇和
酪氨酸激酶抑制剂,已显示减少神经元缠结密度,神经元损失,
心室扩大,并在人类特发性肺纤维化,改善步态速度和其他
功能能力。基于这些发现,我们假设黄烷醇、槲皮素和酪氨酸激酶
抑制剂达沙替尼(Q+D)将改善NVC对执行任务的反应,降低循环SASP
成分,并在这样做,改善认知和流动性的老年人谁是阿尔茨海默氏症的风险
疾病我们的具体目标是:1)进行一项为期12周的单组、开放标签、前后试验性研究,
确定研究间歇剂量槲皮素和达沙替尼的可行性和招募挑战
(Q+D)12例70 ~ 90岁的老年人,步态速度慢(<1.0 m/sec),轻度认知功能障碍;
2)为了获得Q+D方案对以下方面影响的初步数据:a)静息脑血流量(CBF)和
执行任务期间的神经血管耦合(NVC),B)步态速度和执行功能,以及c)其他
身体和认知表现的次要指标;和3)开发初步证据
关于Q+D是否与a)血清和尿中衰老生物标志物的减少有关
以及B)这些生物标志物的减少是否与血液中的衰老细胞的改善相关,
步态速度和执行功能。这项研究将利用
波士顿胡椒中心和马约诊所为基础的翻译老年科学网络。其结果可能会确定一个
改善老年人脑血流调节、活动性和认知的新方法,以及
防止他们发展成老年痴呆症该研究还可能有助于建立概念验证,
老年人的认知和功能障碍可能部分来自于
衰老细胞,并通过衰老清除剂减轻。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
LEWIS LIPSITZ其他文献
LEWIS LIPSITZ的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('LEWIS LIPSITZ', 18)}}的其他基金
Senolytics to Improve Cognition and Mobility in Older Adults at Risk of Alzheimer’s Disease
Senolytics 可改善有阿尔茨海默病风险的老年人的认知和活动能力
- 批准号:
10551712 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
Improving Safety of Transitions to Skilled Nursing Care Using Video-conferencing
使用视频会议提高向熟练护理过渡的安全性
- 批准号:
9789893 - 财政年份:2018
- 资助金额:
$ 20万 - 项目类别:
Harvard Older Americans Independence Center Grant
哈佛大学美国老年人独立中心拨款
- 批准号:
7935360 - 财政年份:2009
- 资助金额:
$ 20万 - 项目类别:
Harvard Older Americans Independence Center Grant
哈佛大学美国老年人独立中心拨款
- 批准号:
7793863 - 财政年份:2009
- 资助金额:
$ 20万 - 项目类别:
相似国自然基金
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
- 批准号:JCZRQN202500010
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
- 批准号:2025JJ70209
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
- 批准号:
- 批准年份:2024
- 资助金额:0 万元
- 项目类别:面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
- 批准号:2023JJ50274
- 批准年份:2023
- 资助金额:0.0 万元
- 项目类别:省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
- 批准号:
- 批准年份:2022
- 资助金额:33 万元
- 项目类别:地区科学基金项目
补肾健脾祛瘀方调控AGE/RAGE信号通路在再生障碍性贫血骨髓间充质干细胞功能受损的作用与机制研究
- 批准号:
- 批准年份:2022
- 资助金额:52 万元
- 项目类别:面上项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
- 批准号:n/a
- 批准年份:2022
- 资助金额:10.0 万元
- 项目类别:省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
- 批准号:81973577
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
- 批准号:81602908
- 批准年份:2016
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
- 批准号:81501928
- 批准年份:2015
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
相似海外基金
The Phenomenon of Stem Cell Aging according to Methylation Estimates of Age After Hematopoietic Stem Cell Transplantation
根据造血干细胞移植后甲基化年龄估算干细胞衰老现象
- 批准号:
23K07844 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Analysis of Age-dependent Functional Changes in Skeletal Muscle CB1 Receptors by an in Vitro Model of Aging-related Muscle Atrophy
通过衰老相关性肌肉萎缩的体外模型分析骨骼肌 CB1 受体的年龄依赖性功能变化
- 批准号:
22KJ2960 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Joint U.S.-Japan Measures for Aging and Dementia Derived from the Prevention of Age-Related and Noise-induced Hearing Loss
美日针对预防与年龄相关和噪声引起的听力损失而导致的老龄化和痴呆症联合措施
- 批准号:
23KK0156 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Fund for the Promotion of Joint International Research (International Collaborative Research)
The Effects of Muscle Fatigability on Gait Instability in Aging and Age-Related Falls Risk
肌肉疲劳对衰老步态不稳定性和年龄相关跌倒风险的影响
- 批准号:
10677409 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Characterizing gut physiology by age, frailty, and sex: assessing the role of the aging gut in "inflamm-aging"
按年龄、虚弱和性别表征肠道生理学特征:评估衰老肠道在“炎症衰老”中的作用
- 批准号:
497927 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Deciphering the role of osteopontin in the aging eye and age-related macular degeneration
破译骨桥蛋白在眼睛老化和年龄相关性黄斑变性中的作用
- 批准号:
10679287 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Role of AGE/RAGEsignaling as a driver of pathological aging in the brain
AGE/RAGE信号传导作为大脑病理性衰老驱动因素的作用
- 批准号:
10836835 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Elucidation of the protein kinase NLK-mediated aging mechanisms and treatment of age-related diseases
阐明蛋白激酶NLK介导的衰老机制及年龄相关疾病的治疗
- 批准号:
23K06378 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Underlying mechanisms of age-related changes in ingestive behaviors: From the perspective of the aging brain and deterioration of the gustatory system.
与年龄相关的摄入行为变化的潜在机制:从大脑老化和味觉系统退化的角度来看。
- 批准号:
23K10845 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Targeting Age-Activated Proinflammatory Chemokine Signaling by CCL2/11 to Enhance Skeletal Muscle Regeneration in Aging
通过 CCL2/11 靶向年龄激活的促炎趋化因子信号传导以增强衰老过程中的骨骼肌再生
- 批准号:
478877 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Operating Grants