Aging, Oxidative Stress and Cell Death

描述（由申请人提供）： 氧化应激在衰老病因学中的作用研究代表了UTHSCSA二十多年来的多部门和多学科研究领域。这种合作努力导致了重大的研究突破和参与研究人员成功申请外部资金。由该项目和其他当前和以前的项目资助的研究已经导致了许多转基因/基因敲除小鼠模型动物模型的开发，这些模型与上一个资助周期开发的新的和新颖的光学成像方法相结合，用于测试氧化应激通过改变线粒体结构和功能而导致衰老的假设。在该计划项目的前五年中，发表了38篇出版物（~8篇/年），其中4篇已出版，7篇已提交，13篇正在准备手稿 和摘要是这个小组合作的结果。在上一个资助周期中有许多重大发现，包括建立氧化应激诱导的神经细胞依赖性凋亡与衰老之间的直接相关性，证明线粒体DMA的损失与线粒体质量的补偿性增加和溶酶体质量的增加有关，以清除受损的线粒体，发现虽然星形胶质细胞神经元保护在衰老过程中减少，有可能通过线粒体依赖性途径增强老年动物中的星形胶质细胞神经元保护，并且最显著和最出乎意料的是，线粒体中各种抗氧化酶的遗传减少不会对这些动物的寿命产生负面影响;事实上，谷胱甘肽过氧化物酶4表达的减少导致寿命的显著增加。总的来说，这些发现使我们重新评估线粒体氧化应激本身作为衰老过程唯一调节剂的重要性，而不是专注于衰老中年龄依赖性对线粒体应激（即线粒体功能，自噬和凋亡）的贡献。在下一个资助期间，我们的目标是确定负责线粒体对衰老表型的贡献的新机制，包括负责年龄相关性骨质疏松症发展中caspase-2介导的细胞凋亡的机制，衰老如何影响细胞对线粒体DNA耗竭应激的反应，线粒体依赖性凋亡途径的调节是否可以延缓衰老并延长寿命，以及在衰老过程中，神经依赖性代谢的上调是否具有神经保护作用。我们相信，这些研究应该有实际的后果，在确定合理的新药发现在这一领域的分子靶点。

DESCRIPTION (provided by applicant): Study of the role of oxidative stress in the etiology of aging has represented a multi-departmental and multidisciplinary area of research at UTHSCSA for over twenty years. This collaborative effort has resulted in significant research breakthroughs and successful applications for external funding by the participating investigators. Studies funded by this and other current and previous program project grants have led to the development of a number of transgenic/knockout mouse models animal models that coupled with new and novel optical imaging approaches developed in the last funding cycle, were used to test the hypothesis that oxidative stress contributes to aging by altering mitochondrial structure and function. Over the first five years of this program project, 38 publications (~8/year), 4 in press, 7 submitted and 13 in preparation manuscripts and abstracts have resulted from the collaborative work of this group. There were a number of major findings during the previous funding cycle including the establishment of a direct correlation between oxidant stress induced mitochondrial-dependent apoptosis and aging, a demonstration that loss of mitochondrial DMA is associated with a compensatory increase in mitochondrial mass and an increase in lysosomal mass putatively to remove damaged mitochondria, the discovery that while astrocytic neuronal protection decreases during aging, it is possible to enhance astrocytic neuronal protection in an aged animal through a mitochondrial dependent pathway, and most remarkably and unexpectedly of all, that genetically reducing various antioxidant enzymes in the mitochondria did not negatively impact the lifespan of these animals; in fact, a reduction in glutathione peroxidase 4 expression resulted in a significant increase in longevity. Collectively these findings have led us to reassess the importance of mitochondrial oxidative stress per se as the sole regulator of the aging process, and instead to focus on the contributions of age-dependent response to mitochondrial stress (i.e. mitochondrial function, autophagy and apoptosis) in aging. During the next funding period, our objectives are to identify novel mechanisms responsible for mitochondrial contributions to the aging phenotype including mechanisms responsible for caspase-2 medicated apoptosis in the development of age-related osteoporosis, how aging impacts the cellular response to the stress of mito DNA depletion, whether modulation of the mitochondrial dependent-apoptotic pathway can delay aging and extend lifespan, and whether upregulation of mitochondrial-dependent metabolism can be neuroprotective during aging. We believe that these studies should have practical consequences in the identification of molecular targets for rational new drug discovery in this field.