Mitochondrial Antioxidants, Aging and Healthspan

描述(申请人提供)：我们长期项目的续签申请是基于一项高度集中、综合和互动的努力，以检验线粒体抗氧化剂能够抵抗年龄相关疾病并改善哺乳动物多器官系统的健康和功能的假设。这建立在过去的进展基础上，包括观察到过度表达线粒体靶向过氧化氢酶的小鼠延长了寿命，改善了心脏和肌肉的健康，并对上皮癌具有抵抗力。因此，我们越来越关注健康和健康寿命，包括对器官功能下降的急性模型的研究，这些模型可以作为衰老中类似疾病的替代分析。在这个项目中，我们提出了四个项目来将这一方法应用于衰老障碍，其中线粒体活性氧物种(ROS)和ROS诱导的损伤在其中起着重要作用：1)线粒体ROS与心脏衰老；2)线粒体ROS与神经退行性疾病；3)线粒体ROS与衰老中上皮癌的保护；4)线粒体靶向抗氧化剂、衰老与AZT在骨骼肌功能障碍中的作用。这些项目得到了四个核心的支持：1)行政管理；2)小鼠病理生物学；3)蛋白质组学；4)线粒体保护化学。在每个这些项目和核心中，我们都试图了解线粒体ROS在衰老和健康寿命中所起作用的潜在机制，并追求识别线粒体保护性药物以向人类提供这些健康寿命益处的翻译目标。

DESCRIPTION (provided by applicant): This application for renewal of our longstanding Program Project is based on a highly focused, integrated and interactive effort to examine the hypothesis that mitochondrial antioxidants are capable of resisting age-related disease and improving health and function in multiple organ systems in mammals. This builds on past progress, including observations that mice overexpressing mitochondrially targeted catalase have extended lifespan, improved cardiac, and muscle health and resistance to epithelial cancers. We therefore have developed an increasing focus on health and healthspan, including study of acute models of decline in organ function that can serve as surrogate assays for similar disorders in aging. In this Program Project we propose four Projects to apply this approach to disorders of aging in which mitochondrial reactive oxygen species (ROS) and ROS-induced damage play an important role: 1) Mitochondrial ROS and cardiac aging; 2) Mitochondrial ROS and neurodegenerative disease; 3) Mitochondrial ROS and protection from epithelial cancers in aging; 4) Mitochondrial-targeted antioxidants, aging and AZT in skeletal muscle dysfunction. The Projects are supported by four Cores: 1) Administrative; 2) Mouse pathobiology; 3) Proteomics; 4) Mitochondrial protective chemistry. In each of these Projects and Cores we seek to understand the mechanisms underlying the role of mitochondrial ROS in aging and healthspan, as well as pursuing the translational goal of identifying mitochondrial protective drugs to deliver these healthspan benefits to humans.