Aging, Oxidative Stress and Cell Death

描述(申请人提供)：二十多年来，氧化应激在衰老病因学中的作用的研究代表了UTHSCSA的一个多部门和多学科的研究领域。这一合作努力取得了重大研究突破，并成功地申请了参与调查人员的外部资金。这项研究以及其他当前和以前的计划项目资助导致了一些转基因/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的光学成像方法相结合，被用来检验氧化应激通过改变线粒体结构和功能而导致衰老的假设。在该方案项目的头五年中，38份出版物(约8份/年)，4份在印，7份已提交，13份在准备稿件中 摘要是该小组合作工作的成果。在上一个资金周期中有许多主要发现，包括建立氧化应激诱导的线粒体依赖的细胞凋亡和衰老之间的直接关联，证明线粒体DMA的丧失与线粒体质量的代偿性增加和溶酶体质量的增加可能有助于移除受损的线粒体，发现虽然星形细胞神经元的保护在衰老过程中降低，但有可能通过线粒体依赖的途径加强老年动物的星形胶质细胞神经元保护，最显著和出人意料的是，通过基因减少线粒体中的各种抗氧化酶没有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表达的减少导致了寿命的显著延长。总而言之，这些发现使我们重新评估了线粒体氧化应激本身作为衰老过程唯一调节因子的重要性，转而专注于对线粒体应激(即线粒体功能、自噬和细胞凋亡)的年龄依赖性反应在衰老中的贡献。在下一个资金阶段，我们的目标是确定线粒体导致衰老表型的新机制，包括caspase-2介导的细胞凋亡在老年性骨质疏松症发生中的作用机制，衰老如何影响细胞对mito DNA耗竭的应激反应，线粒体依赖-凋亡途径的调节是否可以延缓衰老和延长寿命，以及线粒体依赖的代谢上调是否可以在衰老过程中起到神经保护作用。我们认为，这些研究将对该领域合理的新药发现的分子靶点的确定具有实际意义。

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.