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.

摘要 在脆弱的发展过程中，一个鲜为人知的特征是生命中最早的时间点 哪个弱点最先被观察到(即，脆弱的开始)。认识到这一关键时间点的意义在于它 有可能发现与脆弱前状态相关的生物机制，并及时启动 预防脆弱的干预措施。最近，我们对小鼠脆弱表型的研究，从 人类脆弱性评估工具(Fry的脆弱性表型)表明，C57BL/6小鼠模型的脆弱性即 在人类身上观察到的。因此，我们有一个鼠标评估工具，它有可能捕捉到脆弱的开始 以及相关的生物特征，如身体功能，以及细胞和分子生物标记物。低- 等级炎症被认为是虚弱的潜在机制；然而，是否虚弱的开始尚不清楚。 与炎症状态增强有关。如果炎症是虚弱的根源， 在健康下降的早期阶段，调节炎症可能是最有效的，而此时 生物体的补偿能力并没有完全耗尽。在强劲的初步数据推动下，我们 将检验全身性炎症是调节 骨骼肌中蛋白质降解途径的激活导致脆弱的发生 肌肉功能和表现下降。目标1将确定虚弱的开始和死亡风险 在雄性和雌性小鼠中设计的实验旨在更好地了解小鼠的脆弱程度 表型提供了对整个寿命的脆弱程度的严格测试，以及神经肌肉的变化 行为表现识别最早出现脆弱标志物的时间点，使用两个临床前 动物模型：C57BL/6和Ames侏儒小鼠。同时，我们将整合对 记忆力和炎症性特征可能会导致健康随着年龄的增长而下降。AIM 2中的实验将 描述骨骼肌健康在多大程度上有助于C57BL/6小鼠的虚弱发展。 我们的初步数据表明，虚弱小鼠在发病年龄的肌肉处于分解代谢状态， 炎性应激增加，肌肉收缩能力受损，基因表达改变(RNA-seq图谱)。至 扩展我们关于肌肉在脆弱开始时的作用的初步证据，我们将检查肌肉功能，肌肉 年龄匹配的虚弱和健壮、非虚弱小鼠的蛋白质降解、转录组和炎症特征。在… 本项目的完成，我们将：1)确认并推广了小鼠的脆弱表型作为可靠的 确定虚弱发病的工具；2)详细了解系统性炎症是否是引发 脆弱；3)在细胞和分子细节上知道骨骼肌是否是导致这种下降的主要驱动因素 在体能方面表现虚弱；以及4)更好地理解了生殖的贡献 荷尔蒙和性脆弱悖论。