SIRT as a regulator of health and lifespan of mammals

SIRT 作为哺乳动物健康和寿命的调节剂

• 批准号: 8048190
• 负责人: DAVID A. SINCLAIR
• 金额: $ 32.4万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048190
• 关键词: Aging; Alzheimer' s Disease; Animal Testing; Animals; Biochemical; Biology of Aging; Blood Glucose; Caenorhabditis elegans; Cells; Cellular biology; Collaborations; Colon; Colon Carcinoma; Data; Diabetes Mellitus; Diet; Disease; Disease Resistance; Distant; Drosophila genus; Electron Transport; Fatty Acids; Fatty acid glycerol esters; Funding; Gene Expression; Genes; Glucose; Glycolysis; Grant; Health; Health Benefit; Heart Diseases; Histopathology; Homologous Gene; House mice; Huntington Disease; Insulin; Insulin-Like Growth Factor I; Knock-out; Knockout Mice; Lead; Life; Longevity; Malignant Neoplasms; Mammals; Measures; Mediating; Memory; Memory Loss; Metabolism; Modeling; Molecular; Mouse Strains; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Obesity; Organism; Pathway interactions; Pharmaceutical Preparations; Physiological; Physiology; Regulation; Research; Research Personnel; Resistance; Resveratrol; Role; Saccharomyces cerevisiae; Science; Series; Signal Transduction; Societies; Staging; Stress; Testing; Tissues; Toxin; Transgenic Mice; Transgenic Organisms; Tumor Suppression; Uncertainty; United States National Institutes of Health; Wood material; Work; adenoma; age related; base; cell type; cost; cytokine; design; dietary restriction; feeding; human FRAP1 protein; improved; insight; mimetics; mouse model; neuroprotection; overexpression; oxidation; prevent; research study; trait

DESCRIPTION (provided by applicant): For over 70 years, researchers have sought to understand of how dietary restriction (DR) extends the lifespan of mammals. In recent years, extra copies of the SIR2 gene have been shown to extend the lifespan in organisms such as baker's yeast, C. elegans and Drosophila, apparently by mimicking DR. Knowing whether the mammalian homolog of SIR2, SIRT1, can mimic DR physiology and extend the lifespan of mammals is one of the most important questions in the aging field today because it could simultaneously lead to new understandings about mammalian aging, about DR physiology, and could lead to drugs that effectively treat the major diseases of society including cancer, neurodegenerative disorders, heart disease and diabetes, not to mention significantly increasing our lifespan. In collaboration with experts in the field, we have begun to answer this question by generating a conditional and tissue-specific SIRT1 overexpressing mouse (SIRT1-Tg) and by treating mice with a SIRT1 activating compound (STAC) called resveratrol. We initiated these experiments over 18 months ago and have generated a large body of data to support this application. We show that resveratrol is mimicking DR in our mice, based on a wide variety of physiological and biochemical changes, including lowering blood glucose, insulin/IGF-1, suppressing cancer, protecting against Alzheimer's and Huntington's disease, depleting fat, and preventing memory loss. At the gene expression level, we show that most of the pathways altered by resveratrol are also altered by a low calorie diet, including IGF-1/mTOR signaling, glycolysis, fatty acid synthesis, electron transport and beta oxidation. We show that SIRT1 causes effects similar to resveratrol. The SIRT1-Tg mice have lower insulin and IGF-1 and show increased resistance to spontaneous colon cancer using the APCmin model. We will explore the mechanism by which SIRT1 and resveratrol suppresses colon cancer, which appears to be though b-catenin signaling. The study is at a stage where there is no doubt important insights will be gained about DR and diseases of aging, such as diabetes, neurodegeneration and cancer. Many of the mice are housed at NIH, not at Harvard, as a cost-saving measure. I request funds to continue this study so that we can test these animals and the SIRT1-Tg for traits seen in DR animals including cytokine alterations, resistance to toxins, increased disease resistance, and slower aging. A conditional SIRT1 knockout mouse has been obtained to understand mechanisms of action by testing whether SIRT1 is required for DR and resveratrol to prevent diabetes, suppress cancer and extend lifespan, and by dissecting the pathways we have already identified as candidates for mediating the health benefits we have seen in our resveratrol-fed and transgenic mice.

描述（由申请人提供）：70多年来，研究人员一直试图了解饮食限制（DR）如何延长哺乳动物的寿命。近年来，SIR2基因的额外拷贝已被证明可以延长生物体的寿命，如面包酵母、隐杆线虫和果蝇，显然是通过模仿DR。了解SIR2的哺乳动物同源物SIRT1是否可以模仿DR生理学并延长哺乳动物的寿命是当今衰老领域最重要的问题之一，因为它可能同时导致对哺乳动物衰老、DR生理学的新理解。并可能导致有效治疗社会主要疾病的药物，包括癌症、神经退行性疾病、心脏病和糖尿病，更不用说显著延长我们的寿命了。通过与该领域的专家合作，我们已经开始通过产生条件和组织特异性SIRT1过表达小鼠（SIRT1- tg）以及用称为白藜芦醇的SIRT1激活化合物（STAC）治疗小鼠来回答这个问题。我们在18个月前开始了这些实验，并生成了大量数据来支持这个应用程序。我们的研究表明，白藜芦醇在我们的小鼠中模仿DR，基于各种生理和生化变化，包括降低血糖、胰岛素/IGF-1、抑制癌症、预防阿尔茨海默氏症和亨廷顿氏病、消耗脂肪和防止记忆丧失。在基因表达水平上，我们发现白藜芦醇改变的大多数途径也会被低热量饮食改变，包括IGF-1/mTOR信号传导、糖酵解、脂肪酸合成、电子传递和β氧化。我们发现SIRT1的作用类似于白藜芦醇。使用APCmin模型，SIRT1-Tg小鼠具有较低的胰岛素和IGF-1，并显示出对自发性结肠癌的抵抗力增加。我们将探索SIRT1和白藜芦醇抑制结肠癌的机制，这似乎是通过b-连环蛋白信号传导。这项研究正处于一个阶段，毫无疑问将获得关于DR和衰老疾病（如糖尿病、神经变性和癌症）的重要见解。为了节省成本，许多老鼠都被安置在NIH，而不是哈佛。我请求资金继续这项研究，以便我们可以测试这些动物和SIRT1-Tg在DR动物中看到的特征，包括细胞因子改变、对毒素的抵抗力、增强的抗病能力和减缓衰老。通过测试DR和白藜芦醇是否需要SIRT1来预防糖尿病、抑制癌症和延长寿命，并通过解剖我们已经确定的途径来介导我们在白藜芦醇喂养和转基因小鼠中看到的健康益处，我们获得了条件SIRT1敲除小鼠，以了解作用机制。