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

项目4：p66Shc(-/-)小鼠的生物能量学、代谢和寿命 P66Shc(-/-)小鼠的寿命延长机制尚不清楚。然而，事实上，这具身体 这些小鼠的体重和线粒体活性氧(ROS)的产生发生了变化，这表明 能量代谢的改变可能是延缓衰老的中心机制 这些动物。身体成分和某些中间代谢酶的活性也 P66Shc(-/-)小鼠与野生型对照相比发生了变化，这进一步支持了这一观点 P66Shc(-/-)小鼠的能量摄入和/或消耗发生改变。长期以来，能量代谢一直是 被认为在老化过程中发挥核心作用，项目4的目的是确定 P66Shc(-/-)小鼠的能量代谢成分发生了变化。活跃率理论将会 预测p66Shc(-/-)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的产生中都起到了作用，所以它是 重要的是检验p66Shc(-/-)小鼠与对照组相比能量代谢降低的假设。至 正确确定p66Shc对能量代谢、全动物、线粒体和 将完成生化测量。我们提出了四个具体目标来确定 P66shc对能量代谢的影响： 具体目标1：测定p66Shc(-/-)和p66Shc(-/-)的全动物24小时和静息能量消耗 野生型小鼠采用间接呼吸量热法。 特定目的2：测定心脏、肝脏和骨骼肌的线粒体质子泄漏动力学 P66Shc(-/-)小鼠和对照组小鼠线粒体。 具体目标3：确定通过主要能量代谢控制通量的酶的活性 P66Shc(-/-)和对照组小鼠心脏、肝脏和骨骼肌中的通路。 具体目标4：在自由饮食和限制40%卡路里的情况下，确定屏障条件下的寿命 P66shc(-/-)、p66shc(+/-)和野生型小鼠。 与公共健康的相关性：这些研究将增加我们对p66Shc在以下方面的影响的了解 能量代谢、ROS产生和寿命；因此/阐明p66Shc在寿命中的作用 在美国，延期很可能与人类健康有关。

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.