Cellular Senescence in Aging-related Metabolic Diseases

衰老相关代谢疾病中的细胞衰老

基本信息

批准号：
9566816
负责人：
YUGUANG SHI
金额：
$ 31.26万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9566816
关键词：
Ablation Acyl Coenzyme A Acyltransferase Adipocytes Adult Aging Alzheimer&apos s Disease Attenuated Biogenesis Biology of Aging Cardiac Myocytes Cardiolipins Cardiomyopathies Cardiovascular Diseases Cardiovascular system Cell Aging Cell Line Cells DNA-Directed DNA Polymerase Data Development Diabetes Mellitus Diabetic Nephropathy Diet Disease Embryo Enzymes Etiology Family Fatty Acids Fibroblasts Functional disorder Genetic Growth Induced Mutation Inflammation Insulin Resistance Knockout Mice Laboratories Link Longevity Luciferases Malignant Neoplasms Metabolic Metabolic Diseases Mitochondria Mitochondrial DNA Modeling Monitor Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidative Phosphorylation Oxidative Stress Pathogenesis Pathogenicity Pathologic Pathway interactions Phospholipids Polyunsaturated Fatty Acids Production Reactive Oxygen Species Reporter Respiration Role Smooth Muscle Myocytes Testing Transgenic Mice Transgenic Organisms Up-Regulation Work age related attenuation base improved in vivo insight mitochondrial DNA mutation mitochondrial dysfunction mutant novel oxidation oxidative damage prevent protein expression response senescence skeletal

项目摘要

Cellular senescence causes inflammation, oxidative stress, and mitochondrial dysfunction, which have been implicated in the pathogenesis of age-related diseases. Accordingly, genetic depletion of senescent cells has recently been shown to extend lifespan and attenuate aging-related diseases. However, the cellular mechanisms underlying senescence and how it may promote diseases of aging are unclear. Recent work from my laboratory has implicated a role for ALCAT1 in linking cellular senescence with aging-related diseases. ALCAT1 is an enzyme that catalyzes pathogenic resynthesis of cardiolipin (CL) with aberrant fatty acids in response to oxidative stress. CL is a mitochondrial signature phospholipid required for oxidative phosphorylation, mitophagy, and mitochondrial biogenesis. Aging is associated with remodeling of CL by polyunsaturated fatty acids (PUFA) that are highly sensitive to oxidative damage by reactive oxygen species (ROS). Our prior work has revealed a key role for ALCAT1 in catalyzing the pathological remodeling of CL by PUFA in aging-related diseases, such as obesity, T2DM, and cardiovascular diseases. ALCAT1 promotes the development of the disorders of aging because its expression is significantly upregulated by ROS, leading to a vicious cycle of oxidative stress, CL oxidation, and mitochondrial dysfunction. Other recent studies from my laboratory also demonstrate a striking role for ALCAT1 in cellular senescence. Our preliminary data indicate that: 1) replicative senescence significantly increases ALCAT1 protein expression; 2) upregulated ALCAT1 expression in cell lines and mice causes mitochondrial DNA (mtDNA) mutation and dysfunction, leading to cellular senescence; and 3) targeted deletion of ALCAT1 delays cellular senescence and prevents the onset of various aging-related diseases, including T2DM, diabetic nephropathy, and cardiomyopathy. Based upon our prior studies and recent findings, we hypothesize that mitochondrial dysfunction by ALCAT1 links cellular senescence to the pathogenesis of aging-related metabolic diseases, which will be tested by three Aims. Aim 1 will elucidate how ALCAT1 promotes mitochondrial dysfunction in replicative senescence, Aim 2 will determine whether mtDNA mutations induced by ALCAT1 links senescence to aging, and Aim 3 will identify the role of ALCAT1 in linking cellular senescence to diet-induced obesity. The results from the proposed studies are expected to provide key insights on targeting ALCAT1 enzyme as a paradigm shifting treatment for aging-related diseases through depletion of senescent cells.

细胞衰老会引起炎症、氧化应激和线粒体功能障碍，这些都与年龄相关疾病的发病机制有关。因此，最近已证明衰老细胞的遗传耗竭可以延长寿命并减轻与衰老相关的疾病。然而，衰老背后的细胞机制以及它如何促进衰老疾病尚不清楚。我实验室最近的工作表明 ALCAT1 在细胞衰老与衰老相关疾病之间的联系中发挥着作用。 ALCAT1 是一种酶，可催化心磷脂 (CL) 与异常脂肪酸的致病性再合成，以响应氧化应激。 CL 是氧化磷酸化、线粒体自噬和线粒体生物发生所需的线粒体特征磷脂。衰老与多不饱和脂肪酸 (PUFA) 的 CL 重塑有关，多不饱和脂肪酸 (PUFA) 对活性氧 (ROS) 的氧化损伤高度敏感。我们之前的工作揭示了 ALCAT1 在肥胖、T2DM 和心血管疾病等衰老相关疾病中通过 PUFA 催化 CL 病理重塑中的关键作用。 ALCAT1 促进衰老疾病的发展，因为 ROS 显着上调其表达，导致氧化应激、CL 氧化和线粒体功能障碍的恶性循环。我实验室最近的其他研究也证明了 ALCAT1 在细胞衰老中的显着作用。我们的初步数据表明：1）复制衰老显着增加 ALCAT1 蛋白表达； 2）细胞系和小鼠中ALCAT1表达上调导致线粒体DNA（mtDNA）突变和功能障碍，导致细胞衰老； 3) ALCAT1的靶向缺失可延缓细胞衰老并预防各种与衰老相关的疾病的发生，包括T2DM、糖尿病肾病和心肌病。根据我们之前的研究和最近的发现，我们假设 ALCAT1 引起的线粒体功能障碍将细胞衰老与衰老相关代谢疾病的发病机制联系起来，这将通过三个目标进行测试。目标 1 将阐明 ALCAT1 如何促进复制衰老中的线粒体功能障碍，目标 2 将确定 ALCAT1 诱导的 mtDNA 突变是否将衰老与衰老联系起来，目标 3 将确定 ALCAT1 在细胞衰老与饮食诱导的肥胖联系中的作用。拟议研究的结果预计将为靶向 ALCAT1 酶作为通过消耗衰老细胞来转变治疗衰老相关疾病的范式提供重要见解。