Cellular Senescence in Aging-related Metabolic Diseases

衰老相关代谢疾病中的细胞衰老

• 批准号: 9904308
• 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
• 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/9904308
• 关键词: Ablation; Acyl Coenzyme A; Acyltransferase; Adipocytes; Adult; Aging; Alzheimer' 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

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，衰老细胞的遗传耗竭最近已被证明可以延长寿命并减轻与衰老相关的疾病。然而，衰老的细胞机制以及它如何促进衰老疾病尚不清楚。我的实验室最近的工作暗示了ALCAT 1在将细胞衰老与衰老相关疾病联系起来方面的作用。ALCAT 1是一种酶，其催化心磷脂（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）对CL的重塑相关，PUFA对活性氧（ROS）的氧化损伤高度敏感。我们先前的工作已经揭示了ALCAT 1在催化衰老相关疾病（如肥胖、T2 DM和心血管疾病）中PUFA对CL的病理性重塑中的关键作用。ALCAT 1促进衰老疾病的发展，因为其表达被ROS显著上调，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ALCAT 1在细胞衰老中的惊人作用。我们的初步数据表明：1）复制性衰老显著增加ALCAT 1蛋白表达; 2）细胞系和小鼠中ALCAT 1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）ALCAT 1的靶向缺失延迟细胞衰老并预防各种衰老相关疾病的发生，包括T2 DM，糖尿病肾病和心肌病。基于我们先前的研究和最近的发现，我们假设ALCAT 1导致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。目的1将阐明ALCAT 1如何促进复制性衰老中的线粒体功能障碍，目的2将确定ALCAT 1诱导的mtDNA突变是否将衰老与衰老联系起来，目的3将确定ALCAT 1在将细胞衰老与饮食诱导的肥胖联系起来中的作用。预计拟议研究的结果将为靶向ALCAT 1酶提供关键见解，作为通过耗尽衰老细胞治疗衰老相关疾病的范式转变。