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: 9979231
• 负责人: James P. White
• 金额: $ 24.15万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979231
• 关键词: ATAC-seq; Acute; Address; Affect; Age-Months; Aging; Biological Models; Blood; Blood Circulation; Bone Regeneration; Brain; C57BL/6 Mouse; Cardiac; Cell physiology; 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; 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; regenerative; research study; sarcopenia; satellite cell; stem cells

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损失，简称为骨骼肌。 肌肉减少症，与肌肉力量和活动能力下降、跌倒风险增加以及 无法从损伤中恢复，目前延缓这种情况发生的治疗方法有限。 异时性血液交换对老年接受者具有恢复活力的作用。 增强各种组织的功能，包括骨骼肌和血液。 血浆移植模型是为年老小鼠提供年轻血液循环的既定方法。 然而，这些模型有一些局限性，限制了我们对它们如何进行理解。 这些限制包括由于物理原因而限制数据收集。 寄生虫的附着，了解血液共享的长期影响以及血液共享的必要性 为了消除这些限制，我们对老年小鼠进行了连续血浆注射。 修改了联体共生/脱离模型，允许进行各种寿命/健康寿命测量 因此，R21 的目标是在长期接触年轻血液后的老年小鼠中进行。 应用程序是描述联体共生/脱离模型的特征并确定是否延长（12 数周）肌肉减少症最初发作时的异时性联体共生将改变肌肉的健康寿命 该项目的基本原理是基于初步的。 数据表明，寿命延长、身体机能和再生能力得到改善 异时性联体共生后脱离的小鼠。 异时性联体共生将延长肌肉功能并导致表观遗传重编程 整个肌肉组织和卫星细胞，模拟年轻状态。 追求两个具体目标：目标 1 将确定长期暴露在年轻循环中是否可以 延迟吻合期间肌肉减少症的发展并在脱离后继续。 肌肉健康寿命将通过测量肌肉质量来研究， 运动/收缩功能和再生能力将决定是否延长。 暴露在年轻的循环中可以改变老年人的整个肌肉和卫星细胞的表观遗传学 小鼠在 20-23 个月大时会经历异时或等时共生， 旨在让老小鼠在肌肉减少症发作时接触年轻的血液循环。 分子测量将在联体共生期间和脱离后一个月进行。 该项目在修改后的联体共生/分离模型的实用性方面具有高度创新性，该模型将允许 调查对健康寿命和表观遗传学的长期影响。 意义重大，因为它将解决过去几年中持续存在的知识差距 由于当前模型的局限性，需要数十年才能分离异时性联体共生。 配对将使我们能够研究暴露在年轻循环中是否可以“重置”生理 通过表观遗传重编程控制衰老小鼠的时钟。