Mitochondrial biogenesis, genetics and cell loss in mammalian aging

项目摘要/摘要 线粒体的生物发生是许多衰老干预的目标。而线粒体的诱导 生物发生通常被认为是有益的，我们的数据表明，在 衰老导致线粒体DNA(MtDNA)缺失突变在细胞内积累，并导致 肌肉纤维减少18%，缺乏电子传输链(ETC)的肌肉纤维增加1200% 细分市场。这些效应是拮抗的多效性的；在用药的幼鼠身上没有观察到。基座 根据我们的数据，老年人线粒体生物合成的上调可能会导致显著的骨骼肌 损坏。这些研究将阐明线粒体生物发生在线粒体DNA缺失突变中的作用 积累和评估刺激线粒体生物发生的化合物的老年特异性效应 在骨骼肌中。本项目将：定义肌肉中线粒体生物发生的拮抗多效性 纤维丢失；测试mtDNA缺失基因组积累导致纤维丢失的假设；指定 线粒体生物发生、mtDNA缺失突变积累和细胞之间所需的事件和时间 死亡；完善建议的缺失累积机制；确定基因保护者，哪个目标 线粒体生物发生，拮抗诱导mtDNA缺失突变积累。通过理解 老年诱导线粒体生物发生的机制，我们将明确靶点和治疗方法 减轻对抗影响的策略。这项K02奖，如果得到资助，将保护候选人的研究 从过度延长的临床和行政职责到允许进一步的研究开发的时间。

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.