Anti-aging effects of PGC-1 alpha expression

PGC-1 α表达的抗衰老作用

• 批准号: 7273623
• 负责人: WALTER Frederick WARD
• 金额: $ 5.81万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7273623
• 关键词: Acetylation; Achievement; Activities of Daily Living; Address; Adipose tissue; Affect; Age; Aging; Aging-Related Process; Amino Acids; Animals; Binding; Biogenesis; Biological; Biological Models; Brown Fat; Caloric Restriction; Complex; Cytochrome c1; DNA; DNA Binding; Data; Diquat; Energy Metabolism; Enzymes; Exhibits; Family; Family member; Generations; Genes; Genetic Transcription; Gold; Grant; Gray unit of radiation dose; Hepatic; Homeostasis; Human; Intervention; Isoprostanes; Kidney; Ligands; Link; Lipids; Liver; Longevity; Maintenance; Measures; Mediating; Messenger RNA; Metabolic; Metabolism; Mitochondria; Mitochondrial DNA; Modification; Molecular; Monitor; Mus; Muscle Fibers; Nematoda; Nuclear; Nuclear Hormone Receptors; Organism; Oxidative Stress; PPAR gamma; Paraquat; Peroxisome Proliferator-Activated Receptors; Peroxisome Proliferators; Personal Communication; Physiological; Play; Process; Production; Protein Analysis; Proteins; Quality of life; Range; Rate; Reactive Oxygen Species; Regulation; Relative (related person); Rodent; Role; Signal Pathway; Skeletal Muscle; Standards of Weights and Measures; Structure; Superoxides; Testing; Thermogenesis; Thinking; Thyroid Hormone Receptor; Time; Tissue Differentiation; Tissues; Transcription Coactivator; Transcriptional Regulation; Transgenes; Transgenic Animals; Transgenic Organisms; Western Blotting; Wild Type Mouse; Yeasts; age effect; age related; animal tissue; anti aging; base; carbonyl group; cytochrome c oxidase; gene therapy; glucose metabolism; insight; interest; lipid biosynthesis; lipid metabolism; member; mouse model; novel; programs; protective effect; response; transcription factor; uncoupling protein 1

DESCRIPTION (provided by applicant): The functional capacity of the mitochondrion is actively regulated to meet the energy requirements of mammalian organisms. The regulation of mitochondrial biogenesis involves multiple transcriptional and signaling pathways that modulate the expression of nuclear and mitochondrial genes that are involved in mitochondrial structure, metabolism and proliferation. The transcriptional co activator, peroxisome proliferator-activated receptor-gamma (PPARy) coactivator-1alpha (PGC-1a) is thought to integrate the molecular regulatory circuitry involved in the transcriptional control of cellular energy metabolism, including mitochondrial function and biogenesis. We have developed a unique transgenic mouse model that over-expresses PGC-1a. Preliminary data suggests this animal exhibits metabolic alterations that are analogous to caloric restriction, which has been shown to alter the aging process and extend lifespan. Thus our hypothesis is over-expression of PGC-1a will have an anti-aging action in mice. Mitochondria have been proposed to be an important link between the age-related accumulation of oxidative damage caused by reactive oxygen species and the alterations of physiological function associated with aging. One of the major actions of PGC-1a is the induction of mitochondrial biogenesis. The first specific aim will therefore be to determine if mitochondrial biogenesis has indeed been induced in skeletal muscle, adipose tissue and liver by measuring mitochondrial enzyme and protein levels utilizing real time-PCR for mRNA and Western blot analysis for protein. Specific aim 2 will address the question of whether over-expression of PGC-1a has a protective effect against oxidative damage due to mitochondrial production of reactive oxygen species, as caloric restriction does. Oxidative damage of hepatic lipid, DNA and protein will be determined by measuring isoprostane, oxoSdG and carbonyl group formation, respectively. Specific aim 3 will be a longevity study in which we will determine whether the median life span of the transgenic animals is altered. The long-term objectives of this application are to determine if over-expression of PGC-1a extends the life span of the transgenic animal and, if so, to then determine a mechanism of action for that effect. Insights gained into the mechanisms of life-span extension will increase the likelihood of identifying physiologic or pharmacologic interventions that may enable us to increase human lifespan and/or quality of life. In this context, a better understanding of the molecular processes involved in age-related deteriorative processes, such as oxidative modifications, will uncover approaches for such interventions.

描述（由申请人提供）：主动调节微囊体的功能能力，以满足哺乳动物生物体的能量需求。线粒体生物发生的调节涉及多种转录和信号传导途径，其调节参与线粒体结构、代谢和增殖的核和线粒体基因的表达。转录辅激活因子，过氧化物酶体增殖物激活受体-γ（PPARy）辅激活因子-1 α（PGC-1a）被认为整合了参与细胞能量代谢转录控制的分子调控电路，包括线粒体功能和生物发生。我们已经开发了一种独特的过表达PGC-1a的转基因小鼠模型。初步数据表明，这种动物表现出类似于热量限制的代谢改变，这已被证明可以改变衰老过程并延长寿命。因此，我们假设PGC-1a的过表达将在小鼠中具有抗衰老作用。线粒体被认为是与年龄相关的活性氧引起的氧化损伤的积累和与衰老相关的生理功能改变之间的重要联系。PGC-1a的主要作用之一是诱导线粒体生物合成。因此，第一个具体目标是通过利用mRNA的真实的时间-PCR和蛋白质的Western印迹分析测量线粒体酶和蛋白质水平来确定是否确实在骨骼肌、脂肪组织和肝脏中诱导了线粒体生物合成。具体目标2将解决PGC-1a的过表达是否具有针对由于活性氧的线粒体产生的氧化损伤的保护作用的问题，如热量限制所做的那样。将通过分别测量异前列烷、oxoSdG和羰基形成来确定肝脂质、DNA和蛋白质的氧化损伤。具体目标3将是寿命研究，我们将确定转基因动物的中位寿命是否改变。本申请的长期目标是确定PGC-1a的过表达是否延长转基因动物的寿命，如果是，则确定该作用的作用机制。对寿命延长机制的深入了解将增加确定生理或药理干预措施的可能性，这些干预措施可能使我们能够延长人类寿命和/或生活质量。在这种情况下，更好地了解与年龄相关的恶化过程中所涉及的分子过程，如氧化修饰，将揭示这种干预措施的方法。