Does overexpressing Cu/Zn superoxide dismutase retard aging in rodents

过度表达铜/锌超氧化物歧化酶是否可以延缓啮齿类动物的衰老

• 批准号: 8245578
• 负责人: ARLAN G. RICHARDSON
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245578
• 关键词: Adipose tissue; Age; Aging; Aging-Related Process; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Antioxidants; Atherosclerosis; Biochemical; Breeding; Cardiac; Chronic stress; Cognition; Cuprozinc Superoxide Dismutase; Data; Diet; Disease Progression; Disease model; Environment; Fat-Restricted Diet; Fatty acid glycerol esters; Free Radicals; Gene Combinations; Human; Infectious Agent; Inflammation; Inflammatory; Knockout Mice; Laboratories; Life; Longevity; Mammals; Measures; Metabolic syndrome; Modeling; Molecular; Molecular Profiling; Mus; Obesity; Organism; Oxidative Stress; Pathology; Physiological; Physiological Processes; Play; Population; Rat Strains; Research; Resistance; Rodent; Role; Stress; System; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Trauma; age related; animal tissue; base; catalase; feeding; genetic manipulation; glutathione peroxidase; inflammatory marker; neuromuscular function; overexpression; oxidative damage; prevent; public health relevance; theories

DESCRIPTION (provided by applicant): One of the most widely accepted theories in aging research is the free radical or oxidative stress theory of aging, which argues that the age-related loss of physiological function and age-related increase in pathology are due to the progressive accumulation of oxidative damage. Although this theory is currently one of the most popular explanations for how aging occurs at the biochemical/molecular level, most of the evidence in support of this theory is correlative. Over the past decade our laboratory has measured the lifespans of more than 15 different transgenic and knockout mice with alterations in the antioxidant defense system. Except for mice lacking Cu/ZnSOD, none of the transgenic or knockout mice showed a decrease in lifespan even though these mice showed increased resistance or sensitivity to oxidative stress. These data, which were obtained with aging colonies of mice maintained under optimal husbandry conditions, seriously call into the question the role that oxidative damage/stress plays in the aging process in mammals. However, when transgenic or knockout mice are breed to various age-related disease models (e.g., models of atherosclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis), we observed that the alterations in the antioxidant defense system had an impact on the progression of these diseases as predicted by the oxidative stress theory of aging. More recently, we found that overexpressing Cu/ZnSOD increased the lifespan and reduced the age-related pathology in an obese strain of rats. Based on these observations, we propose that under optimal husbandry conditions, which minimize stress and trauma from infectious agents and other agents (e.g., inflammation), oxidative stress/damage plays a minimal role in longevity and the aging process. However, when mice are maintained under stressful conditions that accelerate aging, alterations in the antioxidant defense system will have an impact on longevity and pathology. In the revised application, we will test the hypothesis that overexpressing Cu/ZnSOD will retard aging and reduce oxidative stress/damage when mice are fed a high-fat diet to induce life-long, a low-grade inflammatory-stress. This hypothesis will be tested in the following Specific Aims: 1. To determine whether overexpressing Cu/ZnSOD alters the lifespan and pathology of high-fat fed vs. low- fat fed mice. 2. To determine whether overexpressing Cu/ZnSOD alters the age-related decline in physiological function in high-fat fed vs. low-fat fed mice. In this Specific Aim, we will measure 3 age-sensitive physiological processes to assess the physiological function of the transgenic and WT mice on the low- and high-fat diets: cardiac function, neuromuscular function, and cognition. 3. To determine whether overexpressing Cu/ZnSOD alters the levels of oxidative stress and inflammation in high-fat fed vs. low-fat fed mice. In this Specific Aim, we will determine whether reduced inflammation and oxidative damage play a role in the mechanism underlying increased lifespan/reduced pathology by measuring markers of inflammation, oxidative damage, expression profiles in tissues of the transgenic and WT mice fed a high-fat or low-fat diet. 4. To determine whether alterations in Cu/ZnSOD expression specifically in adipose tissue provide protection against high-fat induced stress. Transgenic mice overexpressing Cu/ZnSOD in adipose tissue and conditional knockout mice lacking Cu/ZnSOD in adipose tissue will be generated and the effect of these manipulations on various markers of inflammation and oxidative damage in tissues of the mice fed a high- or low-fat diet will be determined. PUBLIC HEALTH RELEVANCE: We hypothesize that environment is a critical factor in the role that oxidative stress/damage plays in aging. In an environment with minimal stress oxidative damage plays little, if any role; aging arises from other factors. However, when an organism is exposed to chronic stress because of the environment and/or genetic manipulation, oxidative stress/damage plays a major role in aging. The effect of overexpressing Cu/ZnSOD will be tested in mice that are maintained over their lifespan under a chronic stress. Such an approach will not only allow us to test our hypothesis, but will provide a model that is more relevant to what humans encounter in their normal environment. These data would provide very important clues in treating and preventing age-related pathological changes associated with metabolic syndrome in the human population.

描述（由申请人提供）： 衰老研究中最广泛接受的理论之一是衰老的自由基或氧化应激理论，它认为与年龄相关的生理功能丧失以及病理学与年龄相关的病理学丧失是由于氧化损伤的逐渐积累。尽管该理论目前是衰老如何在生化/分子水平上发生的最流行的解释之一，但支持该理论的大多数证据都是相关的。在过去的十年中，我们的实验室测量了15多种不同的转基因和基因敲除小鼠的寿命，并随着抗氧化剂防御系统的改变。除了缺乏Cu/ZnSod的小鼠外，尽管这些小鼠对氧化应激的抗性或敏感性增加，但没有任何转基因或基因敲除小鼠的寿命降低。这些数据是通过在最佳饲养条件下维持的小鼠的衰老菌落获得的，认真地提出了一个问题，即氧化损伤/压力在哺乳动物衰老过程中发挥作用的作用。但是，当转基因或基因敲除小鼠被繁殖为各种与年龄相关的疾病模型（例如，动脉粥样硬化的模型，阿尔茨海默氏病和肌萎缩性侧面硬化症）时，我们观察到抗氧化剂防御系统的改变会影响这些疾病的进展，这是由氧化应激理论预测的。最近，我们发现过度表达Cu/ZnSOD会增加寿命，并降低肥胖大鼠菌株中与年龄相关的病理。 基于这些观察结果，我们建议在最佳饲养条件下，从而最大程度地减少了感染力和其他药物（例如炎症）的压力和创伤，氧化应激/损害在寿命和衰老过程中的作用最小。但是，当小鼠保持在加速衰老的压力条件下，抗氧化剂防御系统的改变将对寿命和病理产生影响。在修订后的应用中，我们将检验以下假设：过度表达Cu/ZnSod会延迟衰老并减少小鼠喂食高脂饮食以诱导终身炎性炎症性炎症性压力时的氧化应激/损害。该假设将在以下特定目的中进行检验：1。确定过度表达Cu/ZnSod是否会改变高脂喂养的寿命和病理学与低脂喂养小鼠的寿命和病理。 2。确定过度表达Cu/ZnSod是否会改变与低脂喂养小鼠相对于年龄相关的生理功能下降。在这个具体目的中，我们将测量3个年龄敏感的生理过程，以评估转基因和WT小鼠在低脂饮食中的生理功能：心脏功能，神经肌肉功能和认知。 3。确定过度表达Cu/ZnSod是否会改变高脂喂养的氧化应激和炎症水平与低脂喂养小鼠的水平。在这个具体目的中，我们将通过测量炎症，氧化损伤的标志，转基因和WT小鼠组织中的氧化损伤，表达谱，喂养高脂或低脂饮食来确定减少炎症和氧化损伤是否在增加寿命/降低病理的机制中起作用。 4。确定Cu/ZnSOD表达的改变是否在脂肪组织中特异性表达提供了防止高脂诱导应激的保护。将产生过表达Cu/ZnSOD在脂肪组织中的过表达的小鼠，以及在脂肪组织中缺乏Cu/Znsod的有条件敲除小鼠，将确定这些操纵对喂养高脂饮食的小鼠组织中各种炎症和氧化损伤的影响。 公共卫生相关性： 我们假设环境是氧化应激/损伤在衰老中起作用的关键因素。在最小压力氧化损伤的环境中，氧化损害几乎没有任何作用。衰老来自其他因素。但是，当生物体因环境和/或遗传操作而暴露于慢性应激时，氧化应激/损害在衰老中起主要作用。过表达Cu/ZnSOD过表达的效果将在慢性应激下在其寿命中保持的小鼠进行测试。这种方法不仅可以使我们能够检验我们的假设，而且还将提供与人类在正常环境中遇到的情况更相关的模型。这些数据将提供非常重要的线索，以治疗和预防与人口中与代谢综合征相关的年龄相关的病理变化。