Oxidative Stress and Aging: Integrated Mechanisms

氧化应激与衰老：综合机制

• 批准号: 6471537
• 负责人: KEVIN C KREGEL
• 金额: $ 42.64万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6471537
• 关键词: age difference; aging; animal old age; antioxidants; cell senescence; cellular pathology; cellular respiration; free radical oxygen; heat injury; laboratory rat; oxidative stress; physiologic stressor; superoxide dismutase

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.

描述：（由申请人提供）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 这些与年龄相关的变化尚不清楚，有证据表明这些变化有所增加 活性氧（ROS）的产生和相关的氧化应激。我们 已经证明衰老与应激耐受力降低有关。 我们的试点实验表明，热应激会产生增强的自由基 生成、受损的抗氧化酶 (AE) 谱以及广泛的细胞 年老动物受伤。该提案的目标是研究机制 细胞和亚细胞水平上的 ROS 形成和氧化损伤 确定衰老的有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。指导性的 该研究计划的假设是，衰老的有机体的 应对由于过度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 比较衰老中选定组织的反应性和细胞损伤 对热应激后的幼鼠； (2)确定ROS生成、AE是否存在与年龄相关的差异 热应激后的反应能力和细胞损伤是由于 细胞水平的改变； (3)确定生理压力是否产生与年龄相关的改变 转录因子激活，如果是的话，这些改变是否是 造成氧化损伤的机制的一部分； (4) 在幼年和年老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、 涉及 AE 的分子和新型体内基因转移技术 过度表达以探究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问题 涉及 ROS 生成、氧化损伤和衰老的问题 广泛应用于许多临床问题（癌症、心血管疾病） 疾病、感染性休克、虚弱）在老年人群中。这样做的结果 研究将使我们能够设计新疗法来保护老年人免受 涉及生理压力以及潜在的许多疾病的情况 与衰老有关。