Frailty: Prediction of Onset and Progression

虚弱：发病和进展的预测

• 批准号: 10253486
• 负责人: HOLLY M. BROWN-BORG
• 金额: $ 75.95万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10253486
• 关键词: Age; Aging; Animal Model; Animals; Assessment tool; Behavioral; Biological; C57BL/6 Mouse; Calcium; Characteristics; Complex; Coupled; Data; Degradation Pathway; Development; Dwarfism; Exhibits; Female; Functional disorder; Gender; Gene Expression; Health; Human; Impairment; In Vitro; Inflammation; Inflammatory; Intervention; Investigation; Knowledge; Longevity; Maintenance; Memory; Molecular; Movement; Mus; Muscle; Muscle Proteins; Muscle function; Myosin ATPase; Natural regeneration; Organism; Performance; Personal Satisfaction; Phenotype; Physical Function; Physical Performance; Physiological; Plant Roots; Prevalence; Protein Biosynthesis; Quality of life; Rewards; Role; Signal Pathway; Skeletal Muscle; Societies; Stress; System; Systems Analysis; Testing; Time; Translating; Ubiquitin; Work; adverse outcome; cytokine; design; disability; exhaust; experimental study; frailty; improved; male; mitochondrial dysfunction; molecular marker; mortality risk; mouse model; multicatalytic endopeptidase complex; neuromuscular; pre-clinical; prevent; protein activation; protein degradation; protein profiling; reproductive hormone; resilience; sex; tool; transcriptome; transcriptome sequencing

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.

抽象的 在脆弱的发展中，理解的特征是一生中最早的时间点 首先观察到哪种脆弱（即脆弱的发作）。认识到这个关键时间点的重要性在于 潜力发现与预铁状态相关的生物学机制并及时启动 防止脆弱的干预措施。最近，我们使用鼠标脆弱表型的工作，反向翻译 人类脆弱的评估工具（Fried的脆弱表型）证明了C57BL/6小鼠模型脆弱 在人类中观察到。因此，我们有一个鼠标评估工具，有可能捕获脆弱的发作 以及相关的生物学特征，例如身体功能，细胞和分子生物标志物。低的- 等级炎症被张贴为脆弱的基本机制；但是，未知是否脆弱 与增强的炎症状态有关。如果炎症是虚弱的起源的根源 调节炎症可能在健康下降的早期阶段最有效，当时 生物体的补偿能力并没有完全用尽。在我们强大的初步数据的驱动下，我们 将检验总体假设，即系统注射是调节的主要触发因素 通过激活骨骼肌中蛋白质降解途径的脆弱起源，导致 肌肉功能和性能降低。 AIM 1将确定脆弱和死亡风险的发作 在旨在更好地了解小鼠如何脆弱的实验中，男性和雌性小鼠 表型提供了整个寿命中脆弱的严格测试，以及神经肌肉的变化是否变化 行为绩效确定脆弱标记所表现出的最早时间点，使用两个临床前 动物模型，C57BL/6和AMES矮小鼠。同时，我们将整合 记忆和炎症性可能会导致健康下降随着年龄的增长。 AIM 2中的实验将 描述骨骼肌健康在多大程度上促进C57BL/6小鼠的脆弱性。 我们的初步数据表明，脆弱的发作时代脆弱小鼠的肌肉处于分解代谢状态，有 炎症胁迫增加，肌肉收缩力受损和基因表达改变（RNA-SEQ谱）。到 扩展我们关于肌肉在脆弱发作时的作用的最初证据，我们将检查肌肉功能，肌肉 蛋白质降解，转录组和炎症型在年龄匹配和稳健的非冰路小鼠中。 我们将完成该项目的完成：1）已确认并扩展了鼠标脆弱的表型作为可靠的 确定脆弱发作的工具； 2）详细了解系统性炎症是否是触发主动性的 脆弱； 3）在细胞和分子细节中知道骨骼肌是否是下降的主要驱动力 脆弱的身体表现； 4）对生殖的贡献有了更好的了解 荷尔蒙和性爱的悖论。