Cellular Senescence in Aging-related Metabolic Diseases

衰老相关代谢疾病中的细胞衰老

• 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
• 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' 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，衰老细胞的基因损耗最近被证明可以延长寿命并减轻与衰老有关的疾病。然而，细胞机制背后的衰老和它如何可能促进衰老疾病尚不清楚。我的实验室最近的工作暗示了ALCAT1在细胞衰老与衰老相关疾病之间的作用。ALCAT1是一种酶，在氧化应激反应中催化心磷脂（CL）与异常脂肪酸的致病性再合成。CL是氧化磷酸化、线粒体自噬和线粒体生物发生所必需的线粒体特征磷脂。衰老与多不饱和脂肪酸（PUFA）对活性氧（ROS）的氧化损伤高度敏感的CL重塑有关。我们之前的工作揭示了ALCAT1在衰老相关疾病（如肥胖、2型糖尿病和心血管疾病）中催化PUFA对CL的病理重塑中的关键作用。ALCAT1的表达被ROS显著上调，导致氧化应激、CL氧化、线粒体功能障碍的恶性循环，从而促进衰老疾病的发展。我的实验室最近的其他研究也证明了ALCAT1在细胞衰老中的显著作用。我们的初步数据表明：1)复制性衰老显著增加ALCAT1蛋白的表达；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)靶向删除ALCAT1延缓细胞衰老，防止各种衰老相关疾病的发生，包括T2DM、糖尿病肾病、心肌病。基于我们之前的研究和最近的发现，我们假设ALCAT1的线粒体功能障碍将细胞衰老与衰老相关代谢性疾病的发病机制联系起来，这将通过三个Aims进行验证。Aim 1将阐明ALCAT1如何促进复制性衰老中的线粒体功能障碍，Aim 2将确定ALCAT1诱导的mtDNA突变是否将衰老与衰老联系起来，Aim 3将确定ALCAT1在细胞衰老与饮食诱导的肥胖之间的作用。拟议研究的结果有望为靶向ALCAT1酶提供关键见解，通过消耗衰老细胞作为衰老相关疾病的范式转换治疗。