Bioenergetics, metabolism and lifespan in p66Shc-/- mice

在前一时期，该计划项目表明，She 蛋白的缺乏会强烈改变新陈代谢，减少肥胖并提高高脂肪饮食的存活率，并提高热量限制 (CR) 饮食的抗压能力和中位寿命。 She 缺陷小鼠的代谢变化与 CR 动物中观察到的代谢变化非常相似，并且一致。 She表达在禁食动物中降低。因此，She 缺乏症似乎是 CR 模仿者。 Shc 缺陷小鼠和 CR 小鼠的脂肪酸氧化、生酮、酮体分解代谢、糖异生和氨基酸分解代谢的能力均增强，而糖酵解能力则降低。 She 突变小鼠因突变而降低了 She 水平，CR 也会导致 She 蛋白水平降低。 She蛋白可能在从进食状态向禁食状态的转变中发挥重要作用。特别是，该计划将追求这样的假设：动物需要减少骨骼肌和肝脏等组织中的 She 蛋白，才能正确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，该项目的目的是确定 She 蛋白对高脂肪/高碳水化合物饮食代谢反应的影响，基于 She 的修饰在 CR 代谢反应中的作用，以及诱导 P-氧化、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 和 She 水平降低的影响。该子项目的三个具体目标是（1）确定高脂肪/高碳水化合物饮食的 p66Shc-/- 小鼠抵抗体重增加的机制； (2) 确定 p66Shc-/- 小鼠中低碳水化合物对持续 CR 的代谢反应是否发生改变； (3) 确定饮食可以模仿 p66Shc-/- 小鼠中观察到的代谢变化并延长寿命。拟议的研究将提供有关 She 蛋白对能量代谢和生命氧化影响的新信息。食用需要持续增加脂肪酸氧化的饮食的动物。

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.