DIETARY RESTRICTION, MT DNA ABNORMALITIES, AND AGING

线粒体在衰老过程中的作用经常被提出。 线粒体功能随年龄增长而下降，这可能会导致严重的 消极的结果。有越来越多的证据表明 线粒体DNA(MtDNA)随年龄增长而缺失。这些与年龄相关的 缺失似乎在神经和肌肉中最明显，并保持了很大的 承诺解释老年带来的主要疾病和障碍 这些纸巾。我们建议研究线粒体DNA异常和 与年龄和延年益寿饮食有关的结果 小鼠的限制(DR)。 我们遵循的假设是线粒体DNA异常会引发 生化结果和临床症状的广泛连续体。线粒体DNA 突变和缺失会导致酶活性下降 电子传递系统(BTS)和氧化磷酸化(OXPHOS)。 对DR的研究是由大量最近的证据所推动的，这些证据表明它可以减少 老化啮齿动物的自由基损伤。 为了阐明与年龄相关的线粒体DNA可能的重要性 异常，我们建议实现四个具体目标：#1)到 年龄相关的线粒体DNA缺失的特征在选定的组织中 小鼠，#2)量化个体线粒体DNA异常的丰度 细胞和肌肉纤维，#3)以确定ETS活性水平和 表征与年龄相关的细胞形态变化，以及，#4)至 确定糖尿病视网膜病变对年龄相关线粒体DNA异常和ETS的影响 鼠标中的活动。这些研究应该为以下方面提供关键数据 线粒体DNA异常与线粒体关系的研究 功能，以及衰老的速度。在此背景下研究这种动物模型 与年龄相关的线粒体功能障碍应该提供一个系统，在这个系统中 旨在保护线粒体DNA的治疗干预措施可以开发并 已评估。

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.