Anti-aging effects of PGC-1 alpha expression

PGC-1 α表达的抗衰老作用

• 批准号: 7134145
• 负责人: WALTER Frederick WARD
• 金额: $ 5.99万
• 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/7134145
• 关键词: adipose tissue; aging; biosynthesis; cell senescence; cytochrome c; cytochrome oxidase; enzyme mechanism; free radical oxygen; gene induction /repression; genetic regulatory element; genetically modified animals; laboratory mouse; liver; longevity; mitochondria; mitochondrial DNA; molecular genetics; oxidative stress; paraquat; peroxisome proliferator activated receptor; polymerase chain reaction; striated muscles; western blottings

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(申请人提供)：线粒体的功能能力受到积极的调节，以满足哺乳动物生物体的能量需求。线粒体生物发生的调控涉及多种转录和信号途径，这些途径调控与线粒体结构、代谢和增殖有关的核基因和线粒体基因的表达。PGC-1a是一种转录共激活因子，即过氧化物酶体增殖物激活受体-γ(PPARy)共激活因子-1α(PGC-1a)，被认为整合了参与细胞能量代谢转录调控的分子调控电路，包括线粒体功能和生物发生。我们已经开发出一种独特的转基因小鼠模型，可以过度表达PGC-1a。初步数据表明，这种动物表现出类似于热量限制的代谢变化，这已被证明可以改变衰老过程，延长寿命。因此，我们的假设是PGC-1a的过度表达将在小鼠中起到抗衰老的作用。线粒体被认为是与衰老相关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的生物发生。因此，第一个具体目标将是通过利用实时荧光聚合酶链式反应和蛋白质印迹分析测量线粒体酶和蛋白质水平，确定线粒体生物发生是否确实在骨骼肌、脂肪组织和肝脏中被诱导。具体目标2将解决的问题是，PGC-1a的过度表达是否像热量限制一样，对由于线粒体产生活性氧物种而造成的氧化损伤具有保护作用。肝脏脂质、DNA和蛋白质的氧化损伤将分别通过测量异前列腺素、oxoSdG和羰基的形成来确定。具体目标3将是一项长寿研究，在这项研究中，我们将确定转基因动物的中位寿命是否发生了变化。这项应用的长期目标是确定过表达PGC-1a是否延长了转基因动物的寿命，如果是的话，然后确定该效果的作用机制。对延长寿命机制的洞察将增加确定生理或药物干预措施的可能性，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退化过程所涉及的分子过程，如氧化修饰，将揭示这种干预的方法。