Alterations in membrane composition and function eith calorie restriction

热量限制导致膜成分和功能发生变化

• 批准号: 7496044
• 负责人: JON J. RAMSEY
• 金额: $ 28.45万
• 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: 2007-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496044
• 关键词: Affect; Age of Onset; Aging; Antioxidants; Biochemical; Bioenergetics; C57BL/6 Mouse; Caloric Restriction; Cell membrane; Class; Diet; Dietary Intervention; Electron Transport; Energy Metabolism; Enzymes; Equilibrium; Fatty Acids; Fatty acid glycerol esters; Fish Oils; Free Radicals; Genes; Genetic; Intervention; Ions; Knock-out; Laboratories; Link; Linoleic Acids; Lipid Peroxidation; Lipids; Liver; Longevity; Maintenance; Malnutrition; Measures; Membrane; Membrane Lipids; Membrane Proteins; Mitochondria; Mus; NAD(P)H Dehydrogenase (Quinone); NAD(P)H dehydrogenase (quinone) 1, human; NQO1 gene; Na(+)-K(+)-Exchanging ATPase; Omega-3 Fatty Acids; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; Phospholipids; Plasma; Play; Polyunsaturated Fatty Acids; Process; Production; Proteins; Protons; Quinone Reductases; Reactive Oxygen Species; Research Personnel; Rodent; Role; Site; Skeletal Muscle; Source; Soybean Oil; Sphingomyelinase; System; Testing; Time; Tissues; Ubiquinone; base; beef; design; enzyme activity; feeding; harman; menhaden; mitochondrial membrane; prevent; programs; tallow; theories

DESCRIPTION (provided by applicant): Calorie restriction (CR), without malnutrition, is the only intervention that has consistently been shown to increase maximum life span and prevent or delay the onset of age-associated pathophysiological changes in laboratory rodents. It has been proposed that the degree of membrane fatty acid unsaturation is a major factor contributing to longevity, and that a decrease in membrane unsaturation may be the mechanism for the retardation of aging with CR. Such theories that link membranes to aging solely through modulation of membrane lipid peroxidizability, however, may be too general since they overlook the affect lipid alterations will also have on membrane-linked processes, such as reactive oxygen species (ROS) production and electron transport chain activity. Also, these theories ignore the role membrane proteins play in protecting against oxidative damage. Considering the central role that membranes play in regulating oxidative stress, we hypothesize that CR causes an alteration in plasma and mitochondria! membrane composition that results in a new bioenergetic balance leading to decreases in both ROS production and membrane oxidative damage. We propose three specific aims to test this theory: Specific Aim 1; To determine membrane composition (fatty acids, phospholipids and coenzyme Q) of mitochondrial and plasma membranes from liver and skeletal muscle of control and 40% CR C57BL/6 mice. Comprehensive lipid analysis will be completed to quantify all classes of phospholipids and their constituent fatty acids. Markers of membrane oxidative damage will also be measured. These studies will thoroughly quantify CR-induced changes in membrane lipid composition, and determine if these changes result in a decrease in membrane peroxidizability. Specific Aim 2; To determine if CR induces alterations in mitochondrial and plasma membrane-linked processes in liver and skeletal muscle from control and 40% CR C57BL/6 mice. Membrane-linked processes related to energy expenditure, ROS production, oxidative damage, and antioxidant defenses will be measured. Groups of CR mice will also be fed diets where the fat source is beef tallow (highly saturated), soybean oil (high linoleic acid), or menhaden fish oil (high n-3 polyunsaturated fatty acids) to determine if alterations in membrane fatty acid composition are required for CR-induced changes in mitochondrial and plasma membrane functions. Specific Aim 3: To determine if decreases in membrane long chain polyunsaturated fatty acids or increases in activity of the plasma membrane redox system are required for life span extension with CR. Genetic (fat-1 mice) and dietary interventions will be used to determine if CR-induced changes in n-3 fatty acids, linoleic acid, or membrane saturation are required for life span extension. Also, NAD(P)H-quinone reductase knockout (NQO1 KO) mice will be used to determine if stimulation of the PM redox system is required for life span extension with CR.

描述（由申请人提供）：无营养不良的卡路里限制（CR）是唯一一贯证明可以增加最大寿命并预防或延迟实验室啮齿动物中年龄相关的病理生理变化的干预措施。已经提出，膜脂肪酸的不饱和度是导致寿命的主要因素，并且膜不饱和度的降低可能是Cr衰老的延迟机制。然而，这种理论仅通过调节膜脂质过氧化性来将膜与衰老联系起来，因此可能太笼统了，因为它们忽略了影响脂质变化的影响，这也将对膜连接的过程（例如活性氧（ROS）生产和电子转运链活性。同样，这些理论忽略了膜蛋白在预防氧化损伤方面起作用的作用。考虑到膜在调节氧化应激中所起的核心作用，我们假设CR会导致血浆和线粒体的改变！膜组成导致新的生物能平衡，从而导致ROS产生和膜氧化损伤的降低。我们提出了三个特定的目的来检验这一理论：特定目的1；确定来自肝脏的线粒体和质膜的膜组成（脂肪酸，磷脂和辅酶Q），来自对照的肝脏和骨骼肌以及40％CR C57BL/6小鼠。全面的脂质分析将完成，以量化所有类别的磷脂及其组成脂肪酸。还将测量膜氧化损伤的标记。这些研究将彻底量化CR诱导的膜脂质组成的变化，并确定这些变化是否导致膜过氧化性降低。具体目标2；为了确定CR是否诱导肝脏和质膜连接过程的改变，对照组和40％CR C57BL/6小鼠的骨骼肌肉和骨骼肌的变化。将测量与能量消耗，ROS产生，氧化损伤和抗氧化剂防御的膜相关的过程。 CR小鼠组还将被喂养饮食，其中脂肪源为牛脂（高度饱和），大豆油（高亚油酸）或Menhaden鱼油（高N-3多不饱和脂肪酸），以确定膜脂肪酸组成是否需要CR诱导的线粒体和层状膜含量函数的变化。特定目标3：确定膜长链多不饱和脂肪酸的减小还是质膜氧化还原系统的活动增加，需要使用Cr延长寿命。遗传（脂肪1小鼠）和饮食干预措施将用于确定CR诱导的N-3脂肪酸，亚油酸或膜饱和度是否需要延长寿命。同样，NAD（P）H Quinone还原酶基因敲除（NQO1 KO）将使用CR刺激PM氧化还原系统是否需要使用Cr刺激。