Investigating the interplay between hallmarks of aging; protein glycation, nutrient sensing, and senescence

研究衰老特征之间的相互作用；

• 批准号: 10901045
• 负责人: Cristina Aguayo-Mazzucato
• 金额: $ 44.42万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901045
• 关键词: Acceleration; Adipocytes; Adipose tissue; Advanced Glycosylation End Products; Age; Aging; Alzheimer' s Disease; Appearance; Area; Automobile Driving; Beta Cell; Cardiovascular Diseases; Cell Aging; Cell Separation; Cells; Centenarian; Chemistry; Communication; Data; Development; Diet; Disease; Dose; Etiology; Excision; Functional disorder; Glucose; Glycolysis Pathway; Goals; Health; High Fat Diet; Human; Hypertension; Insulin; Insulin Resistance; Intervention; Investigation; Knowledge; Label; Light; Longevity; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Modeling; Molecular; Mus; Pancreas; Pathology; Pathway interactions; Peripheral; Phenotype; Physiological; Play; Process; Proteins; Public Health; Pyruvaldehyde; Reporter Genes; Reporting; Research; Role; Source; Stress; Structure of beta Cell of islet; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Studies; Tissues; Transgenic Organisms; Work; adverse outcome; age related; cell type; detection of nutrient; functional decline; genetic manipulation; glycation; in vivo; insulin secretion; insulin sensitivity; insulin signaling; metabolic profile; mouse model; normal aging; novel; pathological aging; pharmacologic; proteostasis; senescence

PROJECT SUMMARY Cellular senescence and deregulated nutrient sensing (insulin signaling and/or insulin resistance), two hallmarks of aging, are implicated in the loss of physiological function and etiology of age-related diseases. Advanced glycation end products (AGEs) are a source of increased protein glycation burden, a manifestation of another hallmark of aging, loss of proteostasis. Methylglyoxal (MGO), a reactive precursor to AGEs, influences the pathophysiology of insulin resistance (IR) and cellular senescence. A recent study indicates that IR accelerates β-cell senescence leading to functional decline in pancreatic tissue and worsening metabolic profile. Emerging evidence also suggests that the accumulation of senescent cells in adipose tissue directly regulates the IR phenotypes. Current investigations established the co-occurrence of these two aging hallmarks. However, a major gap in our knowledge exists in understanding the interactions between both the hallmarks and the impact of normal and pathological aging on these interactions. Our long-term goal is to further investigate this emerging and exciting area of research in the context of tissue-specific communication that dictates interactions among aging hallmarks. The present proposal will specifically ask the following critical questions: (a) how do these three hallmarks of aging interact with each other; (b) is there any tissue-specific hierarchy and interdependency between the three hallmarks in different tissues; (c) can multiple interventions which overcome these hallmarks of aging show additive protection to slow aging and age-related diseases. Our central hypothesis is that MGO- induced protein glycation not only acts as an endogenous driver for IR and cellular senescence but also plays a key role in the interplay between these two hallmarks in the adipose tissue and pancreas. We will test the hypothesis by pursuing the following Specific Aims: 1) the role of methylglyoxal in inducing senescence in the pancreatic β-cells and adipose tissue through protein glycation; 2) the role of methylglyoxal in inducing IR in adipose tissue or insulin release from pancreatic β-cells through protein glycation; and 3) investigate the interplay between MGO-induced protein glycation IR and cellular senescence. Preadipocytes and primary β-cells will be used to study the role of MGO in inducing tissue-specific senescence and IR. We will also utilize senolytics to determine the importance of senescent cells in MGO-induced IR. We will also determine the therapeutic potential of combing a novel glycation-lowering cocktail, Gly-Low, with or without a senolytic for their impact on ameliorating IR, senescence, and lifespan in a physiological (high-fat diet) model. A key significance of this work is helping us understand the interconnectivity among MGO-induced protein glycation burden, IR, and cellular senescence, thereby shedding light on how these hallmarks interact with each other under stress conditions and how this knowledge can be used to slow aging and ameliorate age-related diseases.

项目摘要 细胞感应和失控的营养感应（胰岛素信号传导和/或胰岛素抵抗），两个标志 衰老，隐含在与年龄有关疾病的身体机能和病因的丧失中。先进的 糖基化最终产物（年龄）是蛋白质糖基化燃烧增加的来源，另一种的表现 衰老的标志，失去蛋白质的损失。甲基乙二醇（MGO）是年龄的反应性前体，影响了 胰岛素抵抗（IR）和细胞感应的病理生理。最近的一项研究表明IR 加速β细胞的感应，从而导致胰腺组织的功能下降并加剧代谢特征。 新兴的证据还表明，脂肪组织中感觉细胞的积累直接调节 IR表型。当前的调查确定了这两个老龄化标志的同时出现。然而， 我们知识的一个主要差距在于了解标志与影响之间的相互作用 这些相互作用的正常和病理老化。我们的长期目标是进一步调查这一新兴 在组织特定的沟通背景下，令人兴奋的研究领域决定了这之间的相互作用 老化的标志。本提案将特别提出以下关键问题：（a）这三个如何 衰老的标志相互互动； （b）是否有组织特异性的层次结构和相互依赖性 在不同组织中的三个标志之间； （c）可以多次克服这些标志的干预措施 衰老显示对缓慢衰老和与年龄有关的疾病的添加剂保护。我们的中心假设是mgo- 诱导的蛋白质糖化不仅是IR和细胞感应的内源性驱动器，而且还发挥了A 在脂肪组织和胰腺的这两个标志之间的相互作用中的关键作用。我们将测试 通过追求以下特定目的的假设：1）甲基乙二醇在诱导的感应中的作用 胰腺β细胞和脂肪组织通过蛋白质糖化； 2）甲基乙醛在诱导的IR中的作用 脂肪组织或胰岛素通过蛋白质糖化从胰腺β细胞释放； 3）研究相互作用 MGO诱导的蛋白质糖化IR和细胞感应之间。前胞细胞和主要β细胞将是 用于研究MGO在诱导组织特异性感应和IR中的作用。我们还将利用senoloticts 确定感觉细胞在MGO诱导的IR中的重要性。我们还将确定治疗潜力 结合一种新颖的糖化鸡尾酒，gly-low，无论是否有鼻孔的影响 在物理（高脂饮食）模型中改善IR，感应和寿命。这项工作的关键意义 正在帮助我们了解MGO诱导的蛋白质糖基化伯嫩，IR和细胞之间的互连性 感受，从而阐明了这些标志在应力条件下如何相互作用的亮点 如何使用这些知识来减缓衰老和改善与年龄有关的疾病。