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

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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.