BIOENERGETICS, METABOLISMS AND LIFESPAN IN P66SHC(-/-)MICE

项目4：p66 Shc（-/-）小鼠的生物能量学、代谢和寿命 p66 Shc（-/-）小鼠寿命延长的机制尚不清楚。然而，事实上， 这些小鼠的体重和线粒体活性氧（ROS）产生发生了改变， 能量代谢的变化可能是延缓衰老的中心机制， 这些动物。身体组成和某些中间代谢酶的活性也是 与野生型对照组相比，p66 Shc（-/-）小鼠中的p66 Shc（-/-）蛋白表达发生了变化，这进一步支持了以下观点： 能量摄入和/或消耗在p66 Shc（-/-）小鼠中改变。长期以来，能量代谢 被认为在老化过程中发挥核心作用，项目4的目的是确定 在p66 Shc（-/-）小鼠中，能量代谢的组分改变。生存率理论 预测p66 Shc（-/-）小鼠寿命的延长应该与能量的减少有关。 新陈代谢.由于能量代谢似乎在衰老和ROS产生中起作用， 重要的是检验p66 Shc（-/-）小鼠与对照相比能量代谢降低的假设。到 正确确定p66 Shc对能量代谢、整个动物、线粒体和 将完成生化测量。我们提出了四个具体目标，以确定 p66 Shc对能量代谢的影响： 具体目标1：确定p66 Shc（-/-）和p66 Shc（-/-）中的整个动物24小时和静息能量消耗， 野生型小鼠使用间接呼吸量热法。 具体目标2：确定心脏、肝脏和骨骼肌中的线粒体质子泄漏动力学 来自p66 Shc（-/-）和对照小鼠的线粒体。 具体目标3：确定通过主要能量代谢控制通量的酶的活性 p66 Shc（-/-）和对照小鼠的心脏、肝脏和骨骼肌中的信号通路。 具体目标4：确定自由进食和限制40%热量的屏障条件下的寿命 p66 Shc（-/-）、p66 Shc（+/-）和野生型小鼠。 与公共卫生的相关性：这些研究将增加我们对p66 Shc对 能量代谢、ROS产生和寿命;因此/阐明p66 Shc在寿命中的作用 延长可能与美国的人类健康有关。

Project 4: Bioenergetics, metabolism, and lifespan in p66Shc(-/-) mice The mechanism for life span extension in p66Shc(-/-) mice is not known. However, the fact that body weight and mitochondrial reactive oxygen species (ROS) production are altered in these mice suggest that changes in energy metabolism may be a central mechanism contributing to the retardation of aging in these animals. Body composition and the activities of some enzymes of intermediary metabolism are also changed in p66Shc(-/-) mice when compared to wild-type controls, and this further supports the idea that energy intake and/or expenditure are altered in p66Shc(-/-) mice. Energy metabolism has long been considered to play a central role in the aging process, and the purpose of Project 4 is to determine if components of energy metabolism are altered in the p66Shc(-/-) mice. The rate of living theory would predict that increased longevity in the p66Shc(-/-) mice should be associated with a decrease in energy metabolism. Since energy metabolism appears to play a role in both aging and ROS production, it is important to test the hypothesis that energy metabolism is reduced in p66Shc(-/-) mice vs controls. To properly determine the effect of p66Shc on energy metabolism, whole animal, mitochondrial, and biochemical measurements will be completed. We propose four specific aims to determine the effect of p66Shc on energy metabolism: Specific Aim 1: To determine whole animal 24-hour and resting energy expenditure in p66Shc(-/-) and wild-type mice using indirect respiration calorimetry. Specific Aim 2: To determine mitochondrial proton leak kinetics in heart, liver and skeletal muscle mitochondria from p66Shc(-/-) and control mice. Specific Aim 3: To determine the activity of enzymes that control flux through major energy metabolism pathways in heart, liver and skeletal muscle of p66Shc(-/-) and control mice. Specific Aim 4: To determine lifespan under barrier conditions in ad libitum fed and 40% calorie restricted p66Shc(-/-), p66Shc(+/-) and wild-type mice. Relevance to public health: These studies will increase our knowledge about the effects of p66Shc on energy metabolism, ROS production and life span; therefore/the elucidation of the role p66Shc in lifespan extension will likely be relevant to human health in the United States.