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

翻译后摘要：老化对所有组织都有深远的有害影响，特别是在 骨骼肌骨骼肌质量和功能的骨骼肌相关损失，称为 肌肉减少症，与肌肉力量和活动性降低、更大的福尔斯风险有关，以及 无法从伤病中恢复。目前有有限的治疗方法来延迟这种发作。 条件异时血液交换对老年接受者有恢复活力的作用， 增强包括骨骼肌在内的各种组织的功能。共生和血液 血浆转移模型是将年轻的循环输送给老年小鼠的方法。 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导致的数据收集受限。 寄生虫的附着，了解血液共享的长期影响和需要 连续血浆注射给老年小鼠。为了消除这些限制，我们 修改了共生/分离模型，允许各种寿命/健康寿命测量 老年小鼠长期接触年轻人血液后因此，R21的目标是 应用是表征联体共生/分离模型并确定是否延长（12 在肌肉减少症的初始发作时异时共生将改变肌肉的健康状况 以及分离后的表观遗传模式。该项目的理由是基于初步的 数据表明，寿命延长，身体功能和再生能力改善， 异时共生后分离小鼠。因此，我们假设 异时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，模仿年轻的状态。本研究将 追求两个具体的目标：目标1将确定是否长期暴露于年轻的血液循环， 延迟肌肉减少症在悬吊期间的发展，并在脱离后继续。 肌肉健康寿命将通过测量肌肉质量进行研究， 运动/收缩功能和再生能力。目标2将确定是否延长 暴露于年轻的循环可以改变老年人的整个肌肉和卫星细胞的表观遗传学 小鼠小鼠从20 - 23月龄开始经历异时或等时共生， 旨在让年老的老鼠在肌肉减少症发作时接触年轻的血液循环。功能 在联体共生期间和脱离后一个月进行分子测量。 该项目在改良的联体共生/分离模型的实用性方面具有高度创新性， 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一直存在的知识差距 由于现有模型的局限性，分离异时共生的能力 对将使我们能够调查是否暴露于年轻的循环可以“重置”生理 通过表观遗传重编程在衰老的老鼠中建立时钟。

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.