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，该理论认为与年龄相关的生理功能丧失和与年龄相关的病理增加是由于氧化损伤的进行性积累。虽然这一理论是目前在生物化学/分子水平上对衰老如何发生的最流行的解释之一，但支持这一理论的大多数证据都是相关的。在过去的十年中，我们的实验室已经测量了超过15种不同的转基因和基因敲除小鼠的寿命，这些小鼠的抗氧化防御系统发生了变化。除了缺乏Cu/ZnSOD的小鼠外，没有转基因或基因敲除小鼠显示寿命减少，即使这些小鼠显示出对氧化应激的抵抗力或敏感性增加。这些数据是在最佳饲养条件下维持的小鼠老化群体中获得的，严重质疑氧化损伤/应激在哺乳动物衰老过程中的作用。然而，当转基因或基因敲除小鼠被培育成各种年龄相关疾病模型（例如，动脉粥样硬化、阿尔茨海默病和肌萎缩侧索硬化模型），我们观察到抗氧化防御系统的改变对这些疾病的进展有影响，正如衰老的氧化应激理论所预测的那样。最近，我们发现过表达Cu/ZnSOD增加了肥胖大鼠的寿命并减少了与年龄相关的病理学。 基于这些观察结果，我们提出，在最佳饲养条件下，最大限度地减少来自感染因子和其他因子（例如，炎症），氧化应激/损伤在长寿和衰老过程中起最小的作用。然而，当小鼠保持在加速衰老的压力条件下时，抗氧化防御系统的改变将对寿命和病理学产生影响。在修订后的申请中，我们将测试这一假设，即当小鼠被喂食高脂肪饮食以诱导终身的低级炎症应激时，过表达Cu/ZnSOD将延缓衰老并减少氧化应激/损伤。这一假设将在以下具体目标中得到检验：1.确定过表达Cu/ZnSOD是否改变高脂喂养与低脂喂养小鼠的寿命和病理学。 2.确定过表达Cu/ZnSOD是否改变高脂喂养与低脂喂养小鼠中生理功能的年龄相关性下降。在这个特定目标中，我们将测量3个年龄敏感的生理过程，以评估低脂肪和高脂肪饮食的转基因和WT小鼠的生理功能：心脏功能，神经肌肉功能和认知。 3.确定过表达Cu/ZnSOD是否会改变高脂喂养与低脂喂养小鼠的氧化应激和炎症水平。在本特定目标中，我们将通过测量高脂或低脂饮食喂养的转基因和WT小鼠组织中的炎症标志物、氧化损伤、表达谱，确定炎症和氧化损伤的减少是否在寿命延长/病理减少的潜在机制中发挥作用。 4.为了确定是否改变铜/锌超氧化物歧化酶的表达，特别是在脂肪组织提供保护，对高脂诱导的压力。将产生在脂肪组织中过表达Cu/ZnSOD的转基因小鼠和在脂肪组织中缺乏Cu/ZnSOD的条件性敲除小鼠，并将确定这些操作对饲喂高脂或低脂饮食的小鼠的组织中的炎症和氧化损伤的各种标志物的影响。 公共卫生相关性： 我们假设环境是氧化应激/损伤在衰老中发挥作用的关键因素。在压力最小的环境中，氧化损伤几乎没有作用，如果有的话;衰老是由其他因素引起的。然而，当生物体由于环境和/或遗传操纵而暴露于慢性应激时，氧化应激/损伤在衰老中起主要作用。将在小鼠中测试过表达Cu/ZnSOD的效果，所述小鼠在其寿命期间维持在慢性应激下。这种方法不仅可以让我们验证我们的假设，而且可以提供一个与人类在正常环境中遇到的情况更相关的模型。这些数据将为治疗和预防人群中与代谢综合征相关的年龄相关病理变化提供非常重要的线索。