Bioenergetics, metabolism and lifespan in p66Shc-/- mice

p66Shc-/- 小鼠的生物能学、代谢和寿命

• 批准号: 8589542
• 负责人: JON J. RAMSEY
• 金额: $ 25.21万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8589542
• 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.

在之前的一段时间里，该项目已经表明，缺乏She蛋白强烈地改变了新陈代谢，减少了脂肪，提高了高脂肪饮食的存活率，提高了热量限制（CR）饮食的抗逆性和平均寿命。她缺陷小鼠的代谢变化与在CR动物中观察到的非常相似，并且是一致的。在禁食动物中，她的表达减少。因此，她缺乏症似乎是一种模仿cr的疾病。在shc -偏转小鼠和CR小鼠中，脂肪酸氧化、生酮、酮体分解代谢、糖异生和氨基酸分解代谢能力增加，而糖酵解能力下降。由于突变，She突变小鼠的She水平降低，CR也导致She蛋白水平降低。她的蛋白质可能在从进食到禁食的过渡中起重要作用。特别是，该计划将追求这样一个假设：动物需要减少骨骼肌和肝脏等组织中的She蛋白，以适当地适应需要持续增加脂肪酸氧化的饮食条件（CR，低碳水化合物饮食，高脂肪/高碳水化合物饮食等），而正是在这些条件下，Shc对寿命的影响最为明显。因此，本项目的目的集中在确定She蛋白对高脂肪/高碳水化合物饮食的代谢反应的影响，基于She的修饰在CR的代谢反应中所起的作用，以及诱导p氧化能力、酮体代谢和糖异生能力慢性增加的饮食（低碳水化合物）是否可以反映CR的影响和She水平的降低。本子项目的三个具体目标是：(1)确定高脂肪/高碳水化合物饮食下p66Shc-/-小鼠对体重增加的抵抗机制；(2)确定低碳水化合物是否改变了p66Shc-/-小鼠对持续CR的代谢反应；(3)确定饮食可以模拟p66Shc-/-小鼠的代谢变化并延长寿命。这些研究将为She蛋白对能量代谢和生命氧化的影响提供新的信息。需要持续增加脂肪酸氧化的动物的饮食跨度。