PROJECT SUMMARY/ABSTRACT Mitochondrial biogenesis is a target of many aging interventions. While the induction of mitochondrial biogenesis is generally thought to be beneficial, our data indicate that activating mitochondrial biogenesis at old age drives the intracellular accumulation of mitochondrial DNA (mtDNA) deletion mutations and results in an 18% loss of muscle fibers and a 1,200% increase in electron transport chain (ETC) deficient muscle fiber segments. These effects were antagonistically pleiotropic; they were not observed in treated young rats. Based on our data, up-regulation of mitochondrial biogenesis in aged humans may cause significant skeletal muscle damage. These studies will clarify the role of mitochondrial biogenesis in mtDNA deletion mutation accumulation and evaluate the old-age specific effects of compounds that stimulate mitochondrial biogenesis in skeletal muscle. This project will: define the antagonistic pleiotropy of mitochondrial biogenesis in muscle fiber loss; test the hypothesis that mtDNA deletion genome accumulation drives fiber loss; specify the order of events and time required between mitochondrial biogenesis, mtDNA deletion mutation accumulation and cell death; refine proposed mechanisms for deletion accumulation; determine if geroprotectors, which target mitochondrial biogenesis, antagonistically induce mtDNA deletion mutation accumulation. By understanding the mechanisms of inducing mitochondrial biogenesis at old ages, we will specify targets and treatment strategies that mitigate the antagonistic effects. This K02 award, if funded, will protect the candidate's research time from overextended clinical and administrative duties to allow further research development.