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 虚弱进展的一个知之甚少的特征是生命周期内最早的时间点， 首先观察到哪种脆弱性（即，虚弱的开始）。认识到这一关键时间点的意义在于， 有可能发现与虚弱前状态相关的生物学机制并及时启动 预防虚弱的干预措施。最近，我们对小鼠脆弱表型的研究， 人类脆弱性评估工具（Fried脆弱性表型）证明了C57 B1/6小鼠模型脆弱性， 在人类中观察到的。因此，我们有一个小鼠评估工具，有可能捕捉脆弱的开始 以及相关的生物学特征，例如身体功能以及细胞和分子生物标志物。低- 分级炎症被假定为虚弱的潜在机制;然而，虚弱的发作是否 与增强的炎症状态有关。如果炎症是脆弱的根源， 调节炎症可能在健康下降的早期阶段最有效，此时 机体的补偿能力没有完全耗尽。在我们强大的初步数据的推动下，我们 将测试总体假设，即全身性炎症是调节炎症的主要触发因素。 通过激活骨骼肌中的蛋白质降解途径导致虚弱， 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 为了更好地了解老鼠的脆弱性， 表型提供了在整个生命周期中对虚弱的严格测试，以及神经肌肉的变化是否 行为表现确定最早的时间点，在该时间点，虚弱标志物的表现，使用两个临床前 动物模型，C57 B1/6和艾姆斯侏儒小鼠。与此同时，我们将整合评估， 记忆力和炎症特征可能导致健康随着年龄的增长而下降。目标2的实验将 描述骨骼肌健康对C57 B1/6小鼠虚弱发展的贡献程度。 我们的初步数据表明，虚弱小鼠的肌肉在虚弱开始的年龄处于分解代谢状态， 炎症应激增加、肌肉收缩力受损和基因表达改变（RNA-seq图谱）。到 为了扩展我们关于肌肉在虚弱发作时的作用的初步证据，我们将检查肌肉功能，肌肉 蛋白质降解，转录组和炎症谱在年龄匹配的虚弱和健壮，非虚弱小鼠。在 本项目的完成，我们将：1）已经确认并扩展了小鼠脆弱表型作为可靠的 确定虚弱发作的工具; 2）详细了解全身炎症是否是引发 脆弱; 3）了解细胞和分子细节，骨骼肌是否是导致衰退的主要驱动力 在体能与脆弱;和4）已经获得了更好的理解的贡献，生殖 荷尔蒙和性脆弱悖论