Frailty: Prediction of Onset and Progression

虚弱:发病和进展的预测

基本信息

项目摘要

ABSTRACT A poorly understood characteristic in the progression of frailty is the earliest time point within the lifespan at which frailty is first observed (i.e., onset of frailty). The significance of recognizing this critical time point lies in its potential to discover the biological mechanisms associated with the pre-frail status and to initiate timely interventions to prevent frailty. Recently, our work with the mouse frailty phenotype, reverse-translated from human frailty assessment tools (Fried’s frailty phenotype), demonstrate that C57Bl/6 mice model frailty that is observed in humans. Hence, we have a mouse assessment tool that has potential to capture the onset of frailty and the associated biological signatures such as physical function, and cellular and molecular biomarkers. Low- grade inflammation is postulated to be an underlying mechanism of frailty; yet, it is unknown if the onset of frailty is associated with an enhanced inflammatory state. If inflammation is at the root of the genesis of frailty, modulating inflammation is likely to be most effective at the early stage of health decline, at a time when the compensatory capacity of the organism is not completely exhausted. Driven by our robust preliminary data, we will test the overarching hypothesis that systemic inflammation is the primary trigger regulating the genesis of frailty through activation of protein degradation pathways in skeletal muscle, resulting in decreased muscle function and performance. Aim 1 will determine the onset of frailty and the mortality risk in male and female mice in experiments designed to gain a better understanding of how the mouse frailty phenotype provides for rigorous testing of frailty across the lifespan and whether changes in neuromuscular behavioral performance identify the earliest time points at which frailty markers manifest, using two preclinical animal models, the C57Bl/6 and the Ames dwarf mice. At the same time, we will integrate the assessment of memory and the inflammatory profile that likely contribute to health decline with age. Experiments in Aim 2 will delineate the extent to which skeletal muscle health contributes to the development of frailty in C57Bl/6 mice. Our preliminary data suggest that the muscles of frail mice at the age of frailty onset are in a catabolic state, with increased inflammatory stress, impaired muscle contractility, and altered gene expression (RNA-seq profile). To extend our initial evidence on the role of muscle at the onset of frailty, we will examine muscle function, muscle protein degradation, transcriptome and inflammatory profiles in age-matched frail and robust, nonfrail mice. At the completion of this project we will: 1) have confirmed and extended the mouse frailty phenotype as a reliable tool to determine frailty onset; 2) know in detail whether systemic inflammation is a trigger for the initiation of frailty; 3) know in cellular and molecular detail whether skeletal muscle is a primary driver underlying the decline in physical performance with frailty; and 4) have gained a better understanding of the contribution of reproductive hormones and the sex-frailty paradox.
摘要

项目成果

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HOLLY M. BROWN-BORG其他文献

HOLLY M. BROWN-BORG的其他文献

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{{ truncateString('HOLLY M. BROWN-BORG', 18)}}的其他基金

Indians Into Medicine: Native Educator University Research Opportunity in Neuroscience (INMED: NEUROscience)
印度人进入医学:本土教育大学神经科学研究机会(INMED:神经科学)
  • 批准号:
    10056228
  • 财政年份:
    2019
  • 资助金额:
    $ 75.95万
  • 项目类别:
Indians into Medicine: Native Educator University Research Opportunity in Neuroscience (INMED: NEUROscience)
印度人进入医学:本土教育大学神经科学研究机会(INMED:神经科学)
  • 批准号:
    10372778
  • 财政年份:
    2019
  • 资助金额:
    $ 75.95万
  • 项目类别:
Indians into Medicine: Native Educator University Research Opportunity in Neuroscience (INMED: NEUROscience)
印度人进入医学:本土教育大学神经科学研究机会(INMED:神经科学)
  • 批准号:
    10544544
  • 财政年份:
    2019
  • 资助金额:
    $ 75.95万
  • 项目类别:
Fourteenth & Fifteenth International Symposia on Neurobiology & Neuroendocrinology of Aging
第十四
  • 批准号:
    9899821
  • 财政年份:
    2018
  • 资助金额:
    $ 75.95万
  • 项目类别:
12th and 13th International Symposia on Neurobiology and Neuroendocrinology of Ag
第12届和第13届银神经生物学和神经内分泌学国际研讨会
  • 批准号:
    9058973
  • 财政年份:
    2014
  • 资助金额:
    $ 75.95万
  • 项目类别:
Annual Meeting of the American Aging Association
美国老龄化协会年会
  • 批准号:
    8258141
  • 财政年份:
    2011
  • 资助金额:
    $ 75.95万
  • 项目类别:
Biology of Aging Sessions at Meetings of The Gerontological Society of America
美国老年学会会议上的衰老生物学会议
  • 批准号:
    8257377
  • 财政年份:
    2011
  • 资助金额:
    $ 75.95万
  • 项目类别:
Biology of Aging Sessions at Meetings of The Gerontological Society of America
美国老年学会会议上的衰老生物学会议
  • 批准号:
    8334061
  • 财政年份:
    2011
  • 资助金额:
    $ 75.95万
  • 项目类别:
Role of GH on thiol metabolism, stress resistance and aging
GH 对硫醇代谢、应激抵抗和衰老的作用
  • 批准号:
    8323370
  • 财政年份:
    2010
  • 资助金额:
    $ 75.95万
  • 项目类别:
Role of GH on thiol metabolism, stress resistance and aging
GH 对硫醇代谢、应激抵抗和衰老的作用
  • 批准号:
    8149871
  • 财政年份:
    2010
  • 资助金额:
    $ 75.95万
  • 项目类别:

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