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Loss of neuromuscular function and regenerative capacity is a hallmark of aging; however, the cause of this age- related decline and the molecular pathways underlying this process remain unknown and no clinical intervention successfully arrests age-related neuromuscular dysfunction. The long-term objective of this proposal is to develop an effective stem cell-mediated therapy to ameliorate age-related deterioration of neuromuscular function. Our previously published findings show that transplantation of our unique adult multipotent muscle-derived stem/progenitor cells (MDSPCs) from young mice promotes functional peripheral nerve regeneration in mice with a sciatic nerve defect, delays the onset of aging-related diseases, and triples the lifespan in mouse models of progeria. In addition, induced neovascularization in the muscles and brain—where no transplanted cells were detected—strongly suggests a therapeutic paracrine/endocrine mechanism. Most importantly, our recent preliminary results indicate that systemic transplantation of young MDSPCs into naturally aged mice restores peripheral nerve histology and myelination, increases skeletal muscle weight and fiber cross-sectional area, decreases muscle fibrosis, and improves functional mobility and gait. These novel findings strongly suggest that young MDSPCs can modulate the systemic environment of aged animals through secreted rejuvenating factors that activate or inhibit key molecular signaling pathways critical for tissue regeneration. Thus, we hypothesize that young stem cells—or the therapeutic factors they secrete—can be used to treat chronic aging-related neuromuscular impairments. In Aim 1, we will determine to what extent systemic treatment with young MDSPCs can rejuvenate neuromuscular tissue structure and motor function in naturally aged mice by using clinically relevant techniques such as real-time Resonant Reflection Spectroscopy (RRS), muscle contractile force measurement, nerve conduction testing, and longitudinal motor function testing of mobility, gait, and muscle fatigue. In Aim 2, we will identify the underlying molecular mechanism(s) of neuromuscular functional improvements resulting from transplantation of young MDSPCs, using multiplexing-tandem mass spectrometry and [phosphoproteomics], as well as identify proteins circulating in the blood serum involved in this systemic rejuvenation. Aim 3 will uncover key factors secreted by young MDSPCs that drive neuromuscular tissue rejuvenation and improve function using a quantitative multiplex antibody array system. Together, these aims will uncover the mechanisms of young MDSPC-mediated neuromuscular tissue rejuvenation and functional improvements, identify circulating biomarkers that predict neuromuscular health in aged mammals, and facilitate the discovery of novel stem cell–based therapeutic targets for clinical use.