Bioenergetics, metabolism and lifespan in p66Shc-/- mice

p66Shc-/- 小鼠的生物能学、代谢和寿命

• 批准号: 8785093
• 负责人: JON J. RAMSEY
• 金额: $ 22.45万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8785093
• 关键词: Adipose tissue; Age-Months; Aging; Amino Acids; Animals; Attenuated; Biochemical; Bioenergetics; Biological Assay; Body Composition; Brown Fat; Caloric Restriction; Calories; Carbohydrates; Catabolism; Chronic; Comorbidity; Diabetes Mellitus; Diet; Dietary Intervention; Energy Intake; Energy Metabolism; Environment; Enzymes; Epidemic; Experimental Designs; Fasting; Fatty acid glycerol esters; Gluconeogenesis; Glycolysis; Heart; Human; Hydrogen Peroxide; Instruction; Insulin; Investigation; Ketone Bodies; Ketones; Knock-out; Knockout Mice; Lead; Life; Lipids; Liver; Longevity; Measurement; Measures; Metabolic; Metabolism; Microarray Analysis; Mitochondria; Modification; Mus; Mutant Strains Mice; Mutation; Myocardium; Obesity; Outcome; Play; Production; Proteins; Resistance; Role; Skeletal Muscle; Stem cells; Stress; Sucrose; Testing; Time; Tissues; Translating; Weight Gain; Wild Type Mouse; age related; base; combat; dietary restriction; enzyme activity; enzyme pathway; fatty acid oxidation; feeding; healthy aging; ketogenesis; mimetics; oxidation; p66(ShcA) protein; programs; protein expression; resistance mechanism; respiratory; response; self-renewal; stem cell differentiation

In the preceding period, the program project has shown that deficiency in She proteins strongly alters metabolism, decreases adiposity and increases survival on a high-fat diet, and increases stress resistance and median longevity on a calorie-restricted (CR) diet. The metabolic shift in She-deficient mice strongly resembles that observed in CR animals, and consistently. She expression is decreased in fasting animals. Thus, She-deficiency appears to be a CR-mimetic. In both Shc-deflcient and CR mice there is increased capacity for fatty acid oxidation, ketogenesis, ketone body catabolism, gluconeogenesis, and amino acid catabolism, while capacity for glycolysis is decreased. She mutant mice have decreased She levels as a consequence of mutation, and CR also causes decreased levels of She proteins. She proteins may play an important role in transitioning from the fed to fasted state. In particular, the program will pursue the hypothesis that decreases in She proteins in tissues, such as skeletal muscle and liver, are needed for animals to properly adapt to dietary conditions which require a sustained increase in fatty acid oxidation (CR, low-carbohydrate diets, high-fat/high-carbohydrate diets, etc.), and it is under these conditions that the influence of Shc on lifespan is most noticeable. Thus, the aims of this project are focused on determining the influence of She proteins on the metabolic response to high-fat/high-carbohydrate diets, the role She based modifications play in the metabolic response to CR, and whether or not a diet (low-carbohydrate) that induces chronic increases in capacity for P-oxidation, ketone body metabolism and gluconeogenesis can mirror the effects of CR and decreased She levels. The three Specific Aims of this subproject are to (1) determine the mechanism for resistance to weight gain in p66Shc-/- mice on a high-fat/high-carbohydrate diet; (2) determine if low-carbohydrate the metabolic response to sustained CR is altered in p66Shc-/- mice; and (3) determine diets can mimic the metabolic changes observed in the p66Shc-/- mice and increase life span. The proposed studies will provide new information about the influence of She proteins on energy metabolism and life oxidation. span in animals consuming diets which require sustained increases in fatty acid oxidation.

在上一个时期，该计划项目表明，SHE蛋白质的缺乏会强烈改变新陈代谢，降低肥胖性并增加高脂饮食中的生存率，并增加压力抗压力和寿命中位寿命（CR）饮食（CR）饮食。她缺陷小鼠的代谢转移非常类似于在Cr动物中观察到的，并且始终如一。她在禁食动物中的表情下降。因此，她的缺陷似乎是一种模仿。在SHC脱脂型和CR小鼠中，脂肪酸氧化，生酮发生，酮体分解代谢，糖异生和氨基酸分解代谢的能力增加，而糖酵解的能力降低。由于突变，她的突变小鼠降低了她的水平，CR还会导致蛋白质水平降低。她的蛋白质可能在从美联储过渡到禁食状态方面发挥重要作用。特别是，该计划将提出以下假设：动物需要降低组织中的蛋白质（例如骨骼肌和肝脏），才能适当适应饮食状况，这需要持续增加脂肪酸氧化（CR，低碳水化合物饮食，高脂肪/高脂肪/高碳水化合物饮食等），并且在这些条件下，这些条件是不明显的。 Thus, the aims of this project are focused on determining the influence of She proteins on the metabolic response to high-fat/high-carbohydrate diets, the role She based modifications play in the metabolic response to CR, and whether or not a diet (low-carbohydrate) that induces chronic increases in capacity for P-oxidation, ketone body metabolism and gluconeogenesis can mirror the effects of CR and decreased She levels.该副本的三个特定目的是（1）确定高脂/高碳水化合物饮食中p66shc - / - 小鼠体重增加的机制； （2）确定在p66shc - / - 小鼠中，低碳水化合物对持续CR的代谢反应是否改变； （3）确定饮食可以模仿p66SHC - / - 小鼠中观察到的代谢变化，并增加寿命。拟议的研究将提供有关HE蛋白对能量代谢和生命氧化的影响的新信息。消耗饮食的动物中的跨度需要持续增加脂肪酸氧化。