Functional Decline in Low Functioning Older Adults; Role of iron dysregulation
功能低下的老年人的功能衰退;
基本信息
- 批准号:10689810
- 负责人:
- 金额:$ 61.08万
- 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 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAgeAgingAnimalsBindingBiochemicalBiologicalBloodCell AgingCell physiologyCirculationClassificationClinicalClinical Trials DesignCodeDNA strand breakDataDietary intakeElderlyElectron TransportEpigenetic ProcessEtiologyFosteringFutureGenomic InstabilityGoalsHealth behaviorHomeostasisHormonesHumanImpairmentIndividualInterventionIronLinkLongitudinal, observational studyMeasuresMitochondriaMitochondrial DNAMolecularMovementMuscleMuscle FibersMuscle MitochondriaMutationNational Institute on AgingNutrientOxidative StressParticipantPerformancePermeabilityPhysical FunctionPhysical PerformancePhysical assessmentPilot ProjectsPlasmaPlayPredispositionProcessProductionProspective StudiesProtein Export PathwayProtein ImportProteinsRegulationResearchRespirationRoleSignal TransductionSkeletal MuscleSleepStrategic PlanningTFRC geneTestingTimeUnited States National Institutes of HealthVisitWalkingWorkcellular targetingdisabilityexhaustionfollow-upfrataxinfunctional declinehealthy aginghepcidinimprovedlongitudinal, prospective studymetal transporting protein 1mitochondrial dysfunctionmitochondrial permeability transition poremortalitymuscle strengthnegative affectnovel therapeuticsoxidative damagepharmacologicphysically handicappedpre-clinicalpreservationpreventprotein expressionproteostasispublic health prioritiesresilienceskeletal disorderstandard measurestem cellstargeted treatmenttelomerewalking speed
项目摘要
PROJECT SUMMARY/ABSTRACT
Preserving movement-related independence is a clinical and public health priority, as well as a major goal of the
National Institute on Aging and NIH’s strategic plan for research on aging. Our work has demonstrated that low-
functioning (LF) older adults have a more rapid functional decline than those who are high-functioning (HF).
The biological mechanisms that lead to accelerated functional decline in LF older adults remain poorly
understood, and few therapies are available to prevent its progression. As diverse as the etiologies of physical
disability are, a growing body of evidence strongly implicates the mitochondria (Mt) as playing a key role in the
initial onset and progression of functional decline in many individuals. Mitochondrial dysfunction has been directly
linked to accelerate telomere attrition, genome instability, epigenetic alterations, stem cell exhaustion, cellular
senescence, impaired proteostasis, and deregulated nutrient signaling, all key hallmarks of aging. What’s more,
perturbations in cellular and mitochondrial iron transport and handling may contribute to increased mutations
and deletions, which lead to a reduction in mtDNA copy numbers and thereby negatively affect mitochondrial
(Mt) function. Cellular iron import and export are critical for optimal cellular function. Iron levels are modulated
by the hormone hepcidin via binding and subsequent degradation of the iron export protein ferroportin (Fn). Iron
acquisition (import) occurs through transferrin receptor and is highly responsive to intracellular iron levels. We
also have documented increased skeletal muscle Mt iron stores which increased oxidative stress and the
susceptibility of Mt permeability transition pore (PTP) opening (a measure of Mt resiliency) with age.
Based on our pilot data our central hypothesis is that greater circulating hepcidin levels and muscle iron
deregulation (↓Ferroportin → ↑ Cellular and Mt Iron Levels → ↓TfR-1) in LF older adults will lead to Mt dysfunction
(↑Sensitivity to PTP, ↑Deletions/Damage, ↓Mitochondrial Respiration) and accelerated progression of functional
decline in LF compared to HF older adults.
To test our central hypothesis, we will conduct a prospective longitudinal study in which we will follow HF and LF
research participants (70 to 80 years) for 3 years and obtain plasma and skeletal muscle biochemical measures
of iron regulation and mitochondrial dysfunction at baseline and throughout the follow-up period. The Short
Physical Performance Battery (SPPB) will be used to classify LF (SPPB ≤ 9) and HF (SPPB > 10) participants.
We will annually assess the participants’ physical function through established measures (SPPB, 6-minute walk,
and muscle strength). We will assess changes in health behaviors, including activity levels, dietary intake, and
sleep at annual follow-up visits. For the proposed study, we will examine cross-sectional and longitudinal
associations of dysfunctional iron regulation with levels of Mt and physical function. If our hypotheses are correct,
results will be used to design clinical trials testing pharmacologic therapies that target hepcidin and muscle
abnormalities found to be associated with functional decline in LF older adults.
PROJECT SUMMARY/ABSTRACT
Preserving movement-related independence is a clinical and public health priority, as well as a major goal of the
National Institute on Aging and NIH’s strategic plan for research on aging. Our work has demonstrated that low-
functioning (LF) older adults have a more rapid functional decline than those who are high-functioning (HF).
The biological mechanisms that lead to accelerated functional decline in LF older adults remain poorly
understood, and few therapies are available to prevent its progression. As diverse as the etiologies of physical
disability are, a growing body of evidence strongly implicates the mitochondria (Mt) as playing a key role in the
initial onset and progression of functional decline in many individuals. Mitochondrial dysfunction has been directly
linked to accelerate telomere attrition, genome instability, epigenetic alterations, stem cell exhaustion, cellular
senescence, impaired proteostasis, and deregulated nutrient signaling, all key hallmarks of aging. What’s more,
perturbations in cellular and mitochondrial iron transport and handling may contribute to increased mutations
and deletions, which lead to a reduction in mtDNA copy numbers and thereby negatively affect mitochondrial
(Mt) function. Cellular iron import and export are critical for optimal cellular function. Iron levels are modulated
by the hormone hepcidin via binding and subsequent degradation of the iron export protein ferroportin (Fn). Iron
acquisition (import) occurs through transferrin receptor and is highly responsive to intracellular iron levels. We
also have documented increased skeletal muscle Mt iron stores which increased oxidative stress and the
susceptibility of Mt permeability transition pore (PTP) opening (a measure of Mt resiliency) with age.
Based on our pilot data our central hypothesis is that greater circulating hepcidin levels and muscle iron
deregulation (↓Ferroportin → ↑ Cellular and Mt Iron Levels → ↓TfR-1) in LF older adults will lead to Mt dysfunction
(↑Sensitivity to PTP, ↑Deletions/Damage, ↓Mitochondrial Respiration) and accelerated progression of functional
decline in LF compared to HF older adults.
To test our central hypothesis, we will conduct a prospective longitudinal study in which we will follow HF and LF
research participants (70 to 80 years) for 3 years and obtain plasma and skeletal muscle biochemical measures
of iron regulation and mitochondrial dysfunction at baseline and throughout the follow-up period. The Short
Physical Performance Battery (SPPB) will be used to classify LF (SPPB ≤ 9) and HF (SPPB > 10) participants.
We will annually assess the participants’ physical function through established measures (SPPB, 6-minute walk,
and muscle strength). We will assess changes in health behaviors, including activity levels, dietary intake, and
sleep at annual follow-up visits. For the proposed study, we will examine cross-sectional and longitudinal
associations of dysfunctional iron regulation with levels of Mt and physical function. If our hypotheses are correct,
results will be used to design clinical trials testing pharmacologic therapies that target hepcidin and muscle
abnormalities found to be associated with functional decline in LF older adults.
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Relationship between Mitochondrial Quality Control Markers, Lower Extremity Tissue Composition, and Physical Performance in Physically Inactive Older Adults.
- DOI:10.3390/cells12010183
- 发表时间:2023-01-02
- 期刊:
- 影响因子:6
- 作者:Picca, Anna;Triolo, Matthew;Wohlgemuth, Stephanie E. E.;Martenson, Matthew S. S.;Mankowski, Robert T. T.;Anton, Stephen D. D.;Marzetti, Emanuele;Leeuwenburgh, Christiaan;Hood, David A. A.
- 通讯作者:Hood, David A. A.
{{
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 }}
Stephen D Anton其他文献
Stephen D Anton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('Stephen D Anton', 18)}}的其他基金
Tailoring Recruitment Communication using Virtual Human Technology to Increase Participation of Older Minority Adults in Clinical Trials
使用虚拟人技术定制招聘沟通,以增加老年少数族裔成年人对临床试验的参与
- 批准号:
10332981 - 财政年份:2021
- 资助金额:
$ 61.08万 - 项目类别:
Tailoring Recruitment Communication using Virtual Human Technology to Increase Participation of Older Minority Adults in Clinical Trials
使用虚拟人技术定制招聘沟通,以增加老年少数族裔成年人对临床试验的参与
- 批准号:
10674054 - 财政年份:2021
- 资助金额:
$ 61.08万 - 项目类别:
The University of Florida Jacksonville Aging Studies Center (JAX-ASCENT)
佛罗里达大学杰克逊维尔老龄化研究中心 (JAX-ASCENT)
- 批准号:
10212912 - 财政年份:2017
- 资助金额:
$ 61.08万 - 项目类别:
The University of Florida Jacksonville Aging Studies Center (JAX-ASCENT)
佛罗里达大学杰克逊维尔老龄化研究中心 (JAX-ASCENT)
- 批准号:
9981558 - 财政年份:2017
- 资助金额:
$ 61.08万 - 项目类别:
The University of Florida Jacksonville Aging Studies Center (JAX-ASCENT)
佛罗里达大学杰克逊维尔老龄化研究中心 (JAX-ASCENT)
- 批准号:
10474718 - 财政年份:2017
- 资助金额:
$ 61.08万 - 项目类别:
The University of Florida Jacksonville Aging Studies Center (JAX-ASCENT)
佛罗里达大学杰克逊维尔老龄化研究中心 (JAX-ASCENT)
- 批准号:
9371690 - 财政年份:2017
- 资助金额:
$ 61.08万 - 项目类别:
JAX-Mobility Aging Pain Disparities (MAPD): A Feasibility Study.
JAX-移动性老化疼痛差异 (MAPD):可行性研究。
- 批准号:
10267888 - 财政年份:2017
- 资助金额:
$ 61.08万 - 项目类别:
REVIVE - Resveratrol to enhance vitality and vigor in elders
REVIVE - 白藜芦醇增强老年人的活力和活力
- 批准号:
8849377 - 财政年份:2013
- 资助金额:
$ 61.08万 - 项目类别:
REVIVE - Resveratrol to enhance vitality and vigor in elders
REVIVE - 白藜芦醇增强老年人的活力和活力
- 批准号:
8724341 - 财政年份:2013
- 资助金额:
$ 61.08万 - 项目类别:
REVIVE - Resveratrol to enhance vitality and vigor in elders
REVIVE - 白藜芦醇增强老年人的活力和活力
- 批准号:
8578756 - 财政年份:2013
- 资助金额:
$ 61.08万 - 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:
$ 61.08万 - 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:
$ 61.08万 - 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:
$ 61.08万 - 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:
$ 61.08万 - 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:
$ 61.08万 - 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:
$ 61.08万 - 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:
$ 61.08万 - 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:
$ 61.08万 - 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:
$ 61.08万 - 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:
$ 61.08万 - 项目类别:
Operating Grants