Assessing healthspan and epigenetics in aged mice after prolonged exposure to young circulation

评估长期暴露于年轻循环后的老年小鼠的健康寿命和表观遗传学

• 批准号: 10263935
• 负责人: James P. White
• 金额: $ 20.13万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263935
• 关键词: ATAC-seq; Acute; Address; Affect; Age-Months; Aging; Biological Models; Blood; Blood Circulation; Bone Regeneration; Brain; C57BL/6 Mouse; Cardiac; DNA; Data; Data Collection; Development; Epigenetic Process; Experimental Designs; Exposure to; Health Benefit; Injections; Investigation; Knowledge; Liver; Locomotion; Long-Term Effects; Longevity; Measurement; Measures; Methods; Modeling; Molecular; Mus; Muscle; Muscle function; Muscle satellite cell; Parabiosis; Pattern; Physical Function; Physiological; Plasma; Plasma Exchange; Process; Regenerative capacity; Research; Signal Transduction; Skeletal Muscle; Testing; Tissues; age related; aged; base; design; experimental study; fall risk; healthspan; improved; indexing; injury recovery; innovation; muscle aging; muscle form; muscle regeneration; prevent; reduced muscle strength; research study; sarcopenia; satellite cell; stem cell function

Abstract: Aging has profound deleterious effects across all tissues, especially apparent in skeletal muscle. Age-related loss in skeletal muscle mass and function, referred to as sarcopenia, is associated with decreased muscle strength and mobility, greater risk of falls, and an inability to recovery from injury. Currently there are limited therapies to delay the onset of this condition. Heterochronic blood exchange has rejuvenating effects in the old recipient, showing enhancing function in various tissues, including skeletal muscle. The parabiosis and blood plasma transfer models are established methods to deliver youthful circulation to old mice. However, these models have several limitations that restrict our understanding of how they affect the aging process. Such limitations include restricted data collection due to physical attachment of the parabionts, understanding long-term effects of blood sharing and the need for continuous plasma injections to the aged mouse. To eliminate these limitations, we have modified the parabiosis/detachment model, allowing various lifespan/healthspan measurements in aged mice after prolonged exposure to young blood. Therefore, the objective of this R21 application is to characterize the parabiosis/detachment model and determine if prolonged (12 weeks) heterochronic parabiosis at the initial onset of sarcopenia will alter muscle healthspan and epigenetic patterns after detachment. The rationale for the project is based on preliminary data suggesting lifespan extension and improved physical function and regenerative capacity in the detached mice after heterochronic parabiosis. Therefore, we hypothesize prior heterochronic parabiosis will extend muscle function and result in epigenetic reprogramming in whole muscle tissue and satellite cells, emulating a youthful state. This research study will pursue two specific aims: Aim 1 will determine if prolonged exposure to youthful circulation can delay the development of sarcopenia during anastomose and continue after detachment. Muscle healthspan will be investigated through measurement of muscle mass, locomotive/contractile function and regenerative capacity. Aim 2 will determine if prolonged exposure to youthful circulation can alter epigenetics of whole muscle and satellite cells in aged mice. Mice will undergo either heterochronic or isochronic parabiosis from 20-23 months of age, designed to expose the old mouse to youthful circulation at the onset of sarcopenia. Functional and molecular measurements will be taken during parabiosis and one month after detachment. This project is highly innovative in the utility of a modified parabiosis/detach model that will allow investigation of long-term effects on healthspan and epigenetics. The proposed research is significant because it will address gaps in knowledge that have persisted over the past few decades due to limitations in current models. The ability to detach heterochronic parabiosis pairs will allow us to investigate if exposure to young circulation can “reset” the physiological clock in the aged mouse through epigenetic reprogramming.

摘要：衰老对所有组织都有深远的有害影响，尤其是在 骨骼肌。与年龄相关的骨骼肌质量和功能丧失，称为 骨质疏松症，与肌肉力量和灵活性降低，摔倒的风险更大，以及 无法从伤病中恢复。目前，有一些有限的治疗方法可以延缓这种疾病的发生。 条件。异时血液交换对老年受者有年轻化作用，显示 增强各种组织的功能，包括骨骼肌。异种共生与血液 血浆转移模型是为老年小鼠提供年轻血液循环的已建立方法。 然而，这些模型有几个限制，限制了我们对它们如何 影响衰老过程。这些限制包括由于物理原因而限制的数据收集 附属国，了解血液共享的长期影响和需要 给老龄小鼠持续注射血浆。为了消除这些限制，我们有 修改了异生/脱离模型，允许各种寿命/健康跨度测量 在长期暴露于年轻血液后的老龄小鼠中。因此，这一R21的目标是 应用是表征异生/脱离模型，并确定延长(12 最初出现肌肉量减少时的异慢性异种共生将改变肌肉的健康持续时间 以及脱离后的表观遗传模式。该项目的基本原理是基于初步的 数据显示寿命延长，身体机能和再生能力得到改善 异慢性异种异生后分离的小鼠。因此，我们假设之前 异慢性异种共生将延长肌肉功能并导致表观遗传重新编程 整个肌肉组织和卫星细胞，模仿年轻的状态。这项研究研究将 追求两个具体目标：目标1将确定长期接触年轻血液循环是否可以 吻合术中延缓骨质疏松症的发展，并在脱离后继续。 将通过测量肌肉质量来调查肌肉健康持续时间， 运动/收缩功能和再生能力。目标2将决定是否延长 暴露在年轻血液循环中可以改变老年人全肌和卫星细胞的表观遗传学 老鼠。小鼠在20-23个月龄期间将经历异时或等时异种共生， 旨在使老年小鼠在石棺减少症开始时暴露在年轻的循环中。功能性 并在异种共生期间和脱离后一个月进行分子测量。 该项目在使用修改的异生/分离模型方面具有很高的创新性，将允许 对健康寿命和表观遗传学的长期影响的调查。拟议的研究是 意义重大，因为它将解决过去几年来持续存在的知识差距 几十年来，由于目前模型的限制。分离异慢性异型共生的能力 PATS将使我们能够研究暴露在年轻循环中是否可以重新设置生理 通过表观遗传重新编程在衰老的小鼠中打卡。