DIETARY RESTRICTION, MT DNA ABNORMALITIES, AND AGING

线粒体参与衰老过程经常被提出。 线粒体功能随着年龄的增长而下降，这可能会导致严重的 消极的结果。 越来越多的证据表明， 线粒体DNA（mtDNA）缺失与年龄。这些与年龄相关的 缺失似乎在神经和肌肉中最明显， 承诺解释老年带来的主要疾病和障碍， 这些组织。我们建议研究线粒体DNA异常， 与年龄和寿命延长饮食相关的结果 限制性内切酶（DR）。 我们的假设是，线粒体DNA异常可以触发一个 生化结果和临床症状的广泛连续性。的mtDNA 突变和缺失会导致 电子传递系统（BTS）和氧化磷酸化（OXPHOS）。 DR的研究受到最近大量证据的激励，这些证据表明， 衰老啮齿动物的自由基损伤。 为了阐明与年龄相关的mtDNA的可能重要性， 我们建议实现四个具体目标：#1） 在选定的组织中表征年龄相关的mtDNA缺失， 小鼠，#2），以量化个体中mtDNA异常的丰度。 细胞和肌肉纤维，#3）以确定ETS活性水平， 表征与年龄相关的细胞形态学变化，以及#4） 确定DR对年龄相关mtDNA异常和ETS的影响 老鼠的活动 这些研究应该为以下方面提供关键数据： 确定线粒体DNA异常、线粒体 功能和老化速度。研究这个动物模型 与年龄相关的线粒体功能障碍应该提供一个系统， 可以开发旨在保护mtDNA的治疗干预， 评估。

An involvement of mitochondria in aging processes has often been proposed. Mitochondrial function declines with age and this may have serious negative outcomes. There is increasing evidence for an association of mitochondrial DNA (mtDNA) deletions with age. These age-associated deletions appear to be most pronounced in nerve and muscle and hold great promise for explaining the major diseases and disorders old age brings to these tissues. We are proposing to study mtDNA abnormalities and associated outcomes with respect to age and life span-prolonging dietary restriction (DR) in mice. We are guided by the hypothesis that mtDNA abnormalities can trigger a broad continuum of biochemical outcomes and clinical symptoms. The mtDNA mutations and deletions result in decreases in the activity of the electron transport system (BTS) and oxidative phosphorylation (OXPHOS). The study of DR is motivated by extensive recent evidence that it reduces free radical damage in aging rodents. In order to clarify the possible importance of age-related mtDNA abnormalities, we propose to accomplish four Specific Aims: #1) to characterize age-associated mtDNA deletions in selected tissues in the mouse, #2) to quantify the abundance of mtDNA abnormalities in individual cells and muscle fibers, #3) to determine ETS activity levels and characterize age-associated changes in cellular morphology, and, #4) to determine the effect of DR on age-associated mtDNA abnormalities and ETS activities in the mouse. These studies should provide critical data for determining the relationship among mtDNA abnormalities, mitochondrial function, and the rate of aging. Studying this animal model in the context of age-related mitochondrial dysfunction should provide a system in which therapeutic interventions aimed at protecting mtDNA can be developed and evaluated.