权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
Stephen D Anton
金额：
$ 61.08万
依托单位：
UNIVERSITY OF FLORIDA
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：
https://reporter.nih.gov/project-details/10689810
关键词：
Acceleration Age Aging Animals Binding Biochemical Biological Blood Cell Aging Cell physiology Circulation Classification Clinical Clinical Trials Design Code DNA strand break Data Dietary intake Elderly Electron Transport Epigenetic Process Etiology Fostering Future Genomic Instability Goals Health behavior Homeostasis Hormones Human Impairment Individual Intervention Iron Link Longitudinal, observational study Measures Mitochondria Mitochondrial DNA Molecular Movement Muscle Muscle Fibers Muscle Mitochondria Mutation National Institute on Aging Nutrient Oxidative Stress Participant Performance Permeability Physical Function Physical Performance Physical assessment Pilot Projects Plasma Play Predisposition Process Production Prospective Studies Protein Export Pathway Protein Import Proteins Regulation Research Respiration Role Signal Transduction Skeletal Muscle Sleep Strategic Planning TFRC gene Testing Time United States National Institutes of Health Visit Walking Work cellular targeting disability exhaustion follow-up frataxin functional decline healthy aging hepcidin improved longitudinal, prospective study metal transporting protein 1 mitochondrial dysfunction mitochondrial permeability transition pore mortality muscle strength negative affect novel therapeutics oxidative damage pharmacologic physically handicapped pre-clinical preservation prevent protein expression proteostasis public health priorities resilience skeletal disorder standard measure stem cells targeted treatment telomere walking 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.

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：
CELLS
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.