DIETARY MODULATION OF CELLULAR OXIDATIVE STRESS IN AGING

衰老过程中细胞氧化应激的饮食调节

• 批准号: 2683163
• 负责人: RAJINDAR S SOHAL
• 金额: $ 17.6万
• 依托单位: SOUTHERN METHODIST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2683163
• 关键词: DNA damage; Mus musculus; NAD(H) phosphate; age difference; antioxidants; caloric dietary content; catalase; dietary restriction; gene expression; glutathione; glutathione peroxidase; glutathione reductase; hydrogen peroxide; longevity; nicotinamide adenine dinucleotide; northern blottings; nuclear runoff assay; nutrition of aging; nutrition related tag; oxidation reduction reaction; oxidative stress; peroxidation; protein structure function; superoxide dismutase; superoxides

The long-term goal of the proposed studies is to elucidate the relationship between oxidative stress, caloric intake and the aging process. Caloric or dietary restriction is widely recognized to prolong life span and delay the onset of age-associated pathologies in laboratory rodents. Although several hypotheses have been advanced, the nature of the underlying mechanisms is still unclear. The proposed investigation will attempt to determine if prolongation of life span of mice due to dietary restriction is associated with a decrease in the level of oxidative stress. The main hypothesis to be tested is that dietary restriction causes a downward shift in the steady-state level of oxidative stress, which results in a relatively slower accrual of age-associated oxidative molecular damage. The two Specific Aims of this study, designed to test the main hypothesis are: (1) determine if dietary restriction results in direct and reversible lowering of the level of oxidative stress in mice at various ages. This will reveal whether age is a factor in the imposition or reversibility of the dietary-related oxidative stress. (2) determine if dietary restriction results in long-term deceleration of age-related accumulation of oxidative molecular damage. This will indicate if the effects of dietary restriction become progressively less reversible with the increased length of dietary restriction. The level of oxidative stress will be measured in the brain, heart and kidney using a battery of tests for (a) rates of mitochondrial superoxide anion radical and hydrogen peroxide generation, (b) activities of antioxidative enzymes and accumulation/transcription of their respective mRNA's, (c) ratios of redox couples such as GSH (reduced glutathione)/GSSG (oxidized glutathione), NADPH/NADP+ and NADH/NAD+, (d) oxidative damage to DNA proteins and lipids, and (e) susceptibility of tissues to experimentally-induced oxidative stress. The novelty and significance of this study is that it will indicate if dietary restriction causes a relatively immediate decrease in the level of oxidative stress, and if this effect is reversible, and if the degree of reversibility is dependent on the duration of dietary restriction. Such information is essential in understanding the nature of the relationship between dietary restriction, oxidative stress, and aging.

拟议研究的长期目标是阐明 氧化应激、热量摄入与衰老的关系 过程。 热量或饮食限制被广泛认为可以延长 在实验室中延长寿命并延迟与年龄相关的病理的发生 啮齿动物。 尽管已经提出了几种假设，但 其根本机制仍不清楚。 拟议的调查 将尝试确定小鼠寿命的延长是否是由于 饮食限制与体内水平的降低有关 氧化应激。 要检验的主要假设是饮食 限制导致氧化稳态水平下降 压力，导致与年龄相关的累积速度相对较慢 氧化分子损伤。 本研究的两个具体目标，旨在检验主要假设 是：（1）确定饮食限制是否会导致直接和可逆的结果 降低不同年龄小鼠的氧化应激水平。 这 将揭示年龄是否是强加或可逆转的一个因素 与饮食相关的氧化应激。 (2)确定是否限制饮食 导致与年龄相关的氧化积累的长期减缓 分子损伤。 这将表明饮食的影响是否 随着长度的增加，限制的可逆性逐渐减弱 的饮食限制。 将测量大脑、心脏和 使用一系列测试来检测 (a) 线粒体超氧化物速率的肾脏 阴离子自由基和过氧化氢的产生，(b) 的活性 抗氧化酶及其各自的积累/转录 mRNA，(c) 氧化还原对的比率，例如 GSH（还原型谷胱甘肽）/GSSG （氧化型谷胱甘肽）、NADPH/NADP+ 和 NADH/NAD+，(d) 氧化损伤 DNA 蛋白质和脂质，以及 (e) 组织对 实验诱导的氧化应激。 这项研究的新颖性和意义在于，它将表明： 饮食限制会导致相对立即的水平下降 氧化应激，如果这种效应是可逆的，以及如果氧化应激的程度 可逆性取决于饮食限制的持续时间。 这样的 信息对于理解关系的本质至关重要 饮食限制、氧化应激和衰老之间的关系。