Mitochondrial biogenesis, genetics and cell loss in mammalian aging

项目总结/摘要 线粒体生物发生是许多衰老干预的目标。虽然诱导线粒体 生物发生通常被认为是有益的，我们的数据表明，激活线粒体生物发生， 老年驱动线粒体DNA（mtDNA）缺失突变的细胞内积累， 肌肉纤维减少18%，电子传递链（ETC）缺陷的肌肉纤维增加1,200% 片段这些作用具有拮抗多效性;在给药的幼龄大鼠中未观察到。基于 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骨骼肌 损害这些研究将阐明线粒体生物发生在mtDNA缺失突变中的作用 积累，并评估刺激线粒体生物发生的化合物的老年特异性作用 在骨骼肌中。本项目将：明确肌肉线粒体生物合成的拮抗多效性 纤维丢失;检验mtDNA缺失基因组积累驱动纤维丢失的假设;指定 线粒体生物发生、mtDNA缺失突变积累和细胞增殖之间的事件和时间 死亡;完善删除累积的拟议机制;确定老年保护者， 线粒体生物合成，拮抗性诱导mtDNA缺失突变积累。通过了解 诱导老年线粒体生物合成的机制，我们将指定目标和治疗 缓解对抗效应的策略。这个K 02奖，如果资助，将保护候选人的研究 从过度临床和行政职责中抽出时间，以便进行进一步的研究开发。

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.