Oxidative Stress and Aging: Integrated Mechanisms

描述：（由申请人提供）衰老与能力丧失有关 来调节对生理压力的反应。虽然潜在的机制 这些与年龄相关的变化尚不清楚，有证据表明， 产生活性氧（ROS）和相关的氧化应激。我们 已经证明衰老与降低的应激耐受性有关。 我们的初步实验表明，热应激产生增强的自由基， 抗氧化酶（AE）谱受损，以及广泛的细胞 老年动物的伤害本提案的目的是研究 ROS的形成和氧化损伤在细胞和亚细胞水平， 决定着衰老的机体如何应对生理压力。我们还将 通过操纵体内和体内的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。的指导 这项研究计划的假设是，衰老的生物体具有减少的 科普由于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)确定活性氧生成、AE 反应性和细胞损伤在选定的组织衰老比较 对热应激后幼鼠; (2)确定是否与年龄相关的ROS生成差异，AE 反应性和热应激后的细胞损伤是由于 细胞水平的改变; (3)确定生理应激是否产生与年龄相关的改变 在转录因子激活中，如果是，这些改变是否 促进氧化损伤的部分机制; (4)操纵细胞氧化还原状态在年轻和老年动物之前， 热应力的应用。 我们将采用独特的综合方法，包括整个动物，细胞， 涉及AE的分子和新型体内基因转移技术 过度表达以追求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 涉及活性氧产生、氧化损伤和衰老的问题将有 广泛应用于许多临床问题（癌症、心血管疾病、 疾病、败血性休克、虚弱）。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 与衰老有关。

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.