MTDNA DAMAGE AND REPAIR IN CALORIC RESTRICTED MICE

功能性衰老：功能性衰老的遗传、细胞和生化基础氧自由基对DNA造成损伤，主要是对线粒体DNA造成损伤，这种损伤可导致线粒体功能障碍。有人认为线粒体DNA的氧化和这种损伤会导致线粒体功能障碍。有研究表明，氧化线粒体DNA损伤是小鼠年龄相关脑功能丧失的主要原因。到目前为止，热量限制-延长寿命仍然是未知的。使用定量聚合酶链反应的初步研究表明，脑线粒体DNA损伤的基础水平与年龄相关。此外，线粒体抑制剂3-硝基丙酸诱导氧化损伤后，老龄小鼠的修复能力诱导降低。这项初步研究的目的是确定热量限制是否会减少小鼠脑线粒体中的氧化DNA损伤并防止进一步的氧化应激。该假说预测，热量限制将增强线粒体DNA修复能力，从而减少与年龄相关的线粒体DNA损伤积累。为了验证这一假设，将解决以下目标：1)确定衰老和热量限制期间小鼠大脑中线粒体DNA损伤和修复的程度，2)检查热量限制对线粒体抑制剂3-硝基丙酸诱导线粒体DNA氧化损伤的影响，以及3)检查热功能小鼠的线粒体功能。这一试点项目将有助于为一项旨在了解限制热量对延长哺乳动物寿命的影响的研究项目奠定基础。

Functional Senescence: Genetic, cellular and biochemical basis of functional senescence Oxygen radicals cause damage to DNA, primarily to mitochondrial DNA and this damage can lead to mitochondrial dysfunction. It has been suggested that oxidative mitochondrial DNA and this damage can lead to mitochondrial dysfunction. It has been suggested that oxidative mitochondrial DNA damage is a major contributor to age-associated loss of brain function in the mouse. So far, caloric restriction-life span extension remains unknown. Preliminary studies using quantitative polymerase chain reaction show an age-associated increase in basal levels brain mitochondrial DNA damage. In addition, aged mice exhibit a lower repair capacity induction after induction of oxidative damage by the mitochondrial inhibitor 3-nitropropionic acid. The purpose of this pilot study is to determine if caloric restriction reduces oxidative DNA damage in mouse brain mitochondria and prevents further oxidative stress. The hypothesis predicts that caloric restriction will enhance the mitochondrial DNA repair capacity and therefore reduce the age-associated accumulation of mitochondrial DNA damage. To test this hypothesis the following aims will be addressed: 1) Determine the extent of mitochondrial DNA damage and repair in the brain during aging and caloric restriction in mice, 2) Examine the effect of caloric restriction on the induction of oxidative mitochondrial DNA damage by the mitochondrial inhibitor 3-nitropropionic acid, and 3) Examine mitochondrial function in caloric function in caloric mice. This pilot project will assist in laying the foundation for a research project directed towards the understanding of the effect of caloric restriction in the extension of mammalian life span.