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（由申请人提供）：线粒体的功能能力受到积极调节，以满足哺乳动物生物的能量需求。线粒体生物发生的调节涉及多种转录和信号传导途径，这些途径调节与线粒体结构，代谢和增殖有关的核和线粒体基因的表达。转录CO激活剂，过氧化物酶体增殖物激活的受体伽马（PPARY）共激活剂-1Alpha（PGC-1A）被认为整合了参与细胞能量代谢的转录控制的分子调节电路，包括线粒体功能和生物发生。我们开发了一种过表达PGC-1A的独特转基因小鼠模型。初步数据表明，该动物表现出类似于热量限制的代谢改变，该改变已证明会改变衰老过程并延长寿命。因此，我们的假设是PGC-1A的过表达将在小鼠中具有抗衰老作用。线粒体已被认为是由活性氧引起的氧化损伤与年龄相关的氧化损伤积累与与衰老相关的生理功能的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发生。因此，第一个具体目的是确定通过测量线粒体酶和蛋白质水平利用实时PCR用于mRNA和Western Blot分析的蛋白质，是否确实在骨骼肌，脂肪组织和肝脏中诱导了线粒体生物发生。具体目标2将解决PGC-1A过度表达的问题，是否像热限制一样，由于线粒体产生活性氧而对氧化损伤具有保护作用。肝脂质，DNA和蛋白质的氧化损伤将分别测量异丙烷，OxoSDG和羰基组形成确定。具体目标3将是一项寿命研究，我们将确定转基因动物的中位寿命是否改变。该应用程序的长期目标是确定PGC-1A的过表达是否扩展了转基因动物的寿命，如果是，则可以确定其作用机理。获得生命扩展机制的见解将增加鉴定生理或药理干预措施的可能性，这可能使我们能够增加人类的寿命和/或生活质量。在这种情况下，更好地理解与年龄相关的恶化过程（例如氧化修饰）所涉及的分子过程，将发现这种干预措施的方法。