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; 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）：超过70年，研究人员试图了解饮食限制（DR）如何延长哺乳动物的寿命。近年来，Sir2基因的额外副本已显示可在贝克酵母，秀丽隐杆线虫和果蝇等有机体中延长寿命，这显然是模仿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增加我们的寿命。通过与该领域的专家合作，我们开始通过生成条件和组织特异性SIRT1过表达小鼠（SIRT1-TG）以及用SIRT1激活化合物（STAC）（称为白藜芦醇）的小鼠来回答这个问题。我们在18个月前启动了这些实验，并生成了大量数据以支持此应用程序。我们表明白藜芦醇是基于各种生理和生化的变化，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，降低脂肪，降低脂肪，减少脂肪以及防止记忆损失。在基因表达水平上，我们表明，白藜芦醇改变的大多数途径也会因低热量饮食而改变，包括IGF-1/mTOR信号传导，糖酵解，脂肪酸合成，电子传输和β氧化。我们表明SIRT1引起的效果类似于白藜芦醇。 SIRT1-TG小鼠的胰岛素和IGF-1较低，并使用APCMIN模型显示出对自发性结肠癌的耐药性。我们将探讨SIRT1和白藜芦醇抑制结肠癌的机制，这似乎是B-catenin信号传导。这项研究处于毫无疑问，将获得有关衰老的DR和疾病的重要见解，例如糖尿病，神经变性和癌症。许多小鼠被安置在NIH，而不是在哈佛，作为一种节省成本的措施。我要求资金继续这项研究，以便我们可以对这些动物进行测试和SIRT1-TG，以了解在DR动物中看到的特征，包括细胞因子改变，对毒素的耐药性，抗病性增加和衰老较慢。已经获得有条件的SIRT1基因敲除小鼠，以通过测试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，并解剖我们已经确定为介导我们在白菜酚脂肪和转基因的小鼠中介导的候选者的途径来理解作用机制。