Oxidative Stress and Aging: Integrated Mechanisms

描述：(申请人提供)衰老与能力丧失有关 调节对生理压力的反应。虽然潜在的机制 这些与年龄相关的改变尚不清楚，有证据表明 产生活性氧物种(ROS)和相关的氧化应激。我们 已经证明衰老与压力耐受性降低有关。 我们的初步实验表明，热应激会产生增强的自由基。 代，受损的抗氧化酶(AE)谱和广泛的细胞 对年长动物的伤害。这项建议的目标是研究这些机制 在细胞和亚细胞水平上的ROS形成和氧化损伤 确定衰老的生物体如何应对生理压力。我们还将 在体内通过控制氧化还原状态来调节应激反应 动物模型和体外原代细胞培养系统。引路人 这项研究计划的假设是，衰老的有机体 应对因过度生产而产生的生理压力的能力 ROS和伴随的氧化损伤。我们将通过以下方式检验这一假设： (1)确定ROS生成、AE之间的函数关系 衰老中选定组织的反应性和细胞损伤的比较 热应激后的幼年大鼠； (2)确定ROS生成的年龄相关差异，AE 热应激后的反应性和细胞损伤是由于 细胞水平的改变； (3)确定生理压力是否会产生与年龄相关的变化 转录因子的激活，如果是这样，这些改变是否 氧化损伤机制的一部分； (4)操纵幼年和老年动物的细胞氧化还原状态 热应激的应用。 我们将使用一种独特的综合方法，包括整个动物，细胞， 分子和涉及AE的体内基因转移新技术 过度表达以探索应激反应的基本机制。通过使用 最先进的技术，我们将能够解决重要的机械 涉及ROS生成、氧化损伤和衰老的问题 广泛应用于多种临床问题(癌症、心血管疾病 疾病、感染性休克、虚弱)。这样做的结果 研究将使我们能够设计新的疗法来保护老年人免受 涉及生理压力的情况，以及潜在的许多疾病 与衰老相关的。

DESCRIPTION: (provided by applicant) Aging is associated with a loss of ability to modulate responses to physiological stress. While the mechanisms underlying these age-related alterations are unclear, evidence implicates increased generation of reactive oxygen species (ROS) and associated oxidative stress. We have demonstrated that senescence is associated with reduced stress tolerance. Our pilot experiments suggest that heat stress produces augmented radical generation, impaired antioxidant enzyme (AE) profiles, and widespread cellular injury in older animals. The goal of this proposal is to study the mechanisms of ROS formation and oxidative injury at cellular and subcellular levels to determining how the aged organism copes with physiological stress. We will also modulate the stress response by manipulating redox status in both an in vivo animal model and an in vitro primary cell culture system. The guiding hypothesis for this research program is that aging organisms have a reduced ability to cope with physiological stress due to an exaggerated production of ROS and concomitant oxidative damage. We will examine this hypothesis by: (1) determining the functional relationship between ROS generation, AE responsiveness, and cellular injury in selected tissues in senescent compared to young rats following heat stress; (2) determining whether the age-related differences in ROS generation, AE responsiveness, and cellular injury following heat stress are due to alterations at the cellular level; (3) determining whether physiological stress produces age-related alterations in transcription factor activation and, if so, whether these alterations are part of the mechanism contributing to oxidative damage; (4) manipulating cellular redox status in young and old animals before the application of heat stress. We will use a unique integrated approach that includes whole animal, cellular, molecular, and novel in vivo gene transfer techniques involving AE overexpression to pursue basic mechanisms in the stress response. By using state-of-the-art techniques, we will be able to address important mechanistic questions involving ROS generation, oxidative injury, and aging that will have widespread application to numerous clinical problems (cancer, cardiovascular disease, septic shock, frailty) in aged populations. The results of this research will allow us to design new therapies to protect the elderly against situations involving physiological stress, and potentially, many diseases associated with aging.