OXIDATIVE STRESS AND AGING--INTEGRATED MECHANISMS

描述(改编自申请者摘要)：与年龄相关 普遍丧失了对生理反应的调节能力 压力。老年人丧失能力的潜在机制 有机体应对压力的作用尚不清楚，但有证据表明 产生活性氧物种(ROS)和相关的氧化应激。 使用电子顺磁共振波谱，研究人员已经 在幼年和老年大鼠中都定量地证明了热应激 增加一氧化氮和ROS的生成，导致组织氧化 受伤。他们还证明，年龄较大的老鼠明显更少 对反复高温挑战的耐热性比幼年大鼠低 能够产生保护性应激蛋白。试点研究建立 在热应激之后，ROS的产生和死亡率都是 在衰老的老鼠和年轻的老鼠中被夸大了。因此，指导性假设 对于这项研究计划来说，老化的生物体具有降低的能力 应对因ROS和ROS的过度产生而产生的生理压力 伴随而来的氧化损伤。他们将通过以下方式检验这一假设：1) 确定ROS的产生和氧化损伤是否被夸大，并作为一种 后果、发病率和死亡率在高温后增加 衰老大鼠与成熟清醒大鼠和年轻清醒大鼠的应激反应；2)升高 老年大鼠降低氧化应激水平的抗氧化能力 目标是降低发病率和死亡率；以及3) 确定转录调控的缺失是否重要 应激诱导基因发生在老年大鼠身上。 他们将使用一种综合方法，包括整个动物，细胞， 分子，和新的体内基因转移技术，过度表达 抗氧化酶在应激反应中探索基本机制。通过 使用各种最先进的技术，其目的是能够 解决与自由基形成有关的重要机制问题， 氧化应激和衰老将应用于数字临床 问题(中暑、感染性休克、心血管疾病、糖尿病、 脆弱等。)在老年人口中。

DESCRIPTION (Adapted from the Applicant's Abstract): Aging is associated with a general loss of ability to modulate responses to a physiological stress. The mechanisms underlying the loss of the capacity of the aging organism to cope with stress are unclear, but evidence implicates increased generation of reactive oxygen species (ROS) and associated oxidative stress. Using electron paramagnetic resonance spectroscopy the investigators have demonstrated that in both young and old rats heat stress quantitatively increases nitric oxide and ROS generation, leading to oxidative tissue injury. They have also demonstrated that older rats are significantly less thermotolerant to repeated heat challenge than young rats and are less capable of generating protective stress proteins. Pilot studies establish that following heat stress, both ROS production and mortality rates are exaggerated in senescent versus young rats. Thus, 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. They will examine this hypothesis by: 1) determining if ROS production and oxidative injury are exaggerated, and as a consequence, morbidity and mortality rates are increased following heat stress in senescent versus mature and young conscious rats; 2) elevating antioxidant capacity in older rats to reduce the level of oxidative stress with the goal of achieving lower morbidity and mortality rates; and 3) determining if the loss of transcriptional regulation of important stress-induced genes occurs in aged rats. They will use an integrated approach that includes whole animal, cellular, molecular, and novel in vivo gene transfer techniques that overexpress antioxidant enzymes to pursue basic mechanisms in the stress response. By using a variety of state-of-the-art techniques, the intent is to be able to address important mechanistic questions involving free radical formation, oxidant stress, and aging that will have application to numerus clinical problems (heat stoke, septic shock, cardiovascular disease, diabetes, frailty, etc.) in the aged population.