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 细胞衰老和营养感应失调（胰岛素信号传导和/或胰岛素抵抗），两个标志 在衰老的过程中，生理功能的丧失和与年龄有关的疾病的病因都有牵连。先进 糖基化终产物（AGEs）是蛋白质糖基化负荷增加的来源，是另一种糖基化反应的表现。 衰老的标志蛋白质稳定性丧失甲基乙二醛（MGO）是AGEs的活性前体， 胰岛素抵抗（IR）和细胞衰老的病理生理学。最近的一项研究表明， 加速β细胞衰老，导致胰腺组织功能下降和代谢谱恶化。 新出现的证据还表明，脂肪组织中衰老细胞的积累直接调节了 IR表型。目前的研究确定了这两个老化标志的共同发生。然而，在这方面， 我们的知识中存在一个主要的差距，即理解标志和影响之间的相互作用， 正常和病理性衰老的关系。我们的长期目标是进一步研究这种新兴的 在组织特异性通信的背景下，这是一个激动人心的研究领域， 老化的标志本提案将具体提出以下关键问题：（a）这三个问题如何解决？ 衰老的标志相互作用;（B）是否存在任何组织特异性等级和相互依赖性 不同组织中的三个标志之间的差异;（c）可以克服这些标志的多种干预措施 对延缓衰老和与年龄有关的疾病有额外的保护作用。我们的核心假设是，MGO- 诱导的蛋白质糖基化不仅是IR和细胞衰老的内源性驱动因素， 在脂肪组织和胰腺中这两个标志之间的相互作用中起着关键作用。我们将测试 通过追求以下具体目标来研究这一假说：1）甲基乙二醛在诱导衰老中的作用， 胰腺β细胞和脂肪组织通过蛋白质糖化的作用; 2）甲基乙二醛在诱导胰岛素抵抗中的作用， 脂肪组织或通过蛋白质糖化从胰腺β细胞释放胰岛素;和3）研究相互作用 MGO诱导的蛋白质糖基化IR和细胞衰老之间的关系。前脂肪细胞和原代β细胞将被 用于研究MGO在诱导组织特异性衰老和IR中的作用。我们还将利用senolytics， 确定衰老细胞在MGO诱导的IR中的重要性。我们还将确定 结合一种新的降低糖化的鸡尾酒，Gly-Low，与或不与senolytic， 改善生理（高脂饮食）模型中的IR、衰老和寿命。这项工作的一个重要意义是 帮助我们了解MGO诱导的蛋白质糖化负荷，IR和细胞免疫之间的相互联系。 衰老，从而阐明这些标志在压力条件下如何相互作用， 如何利用这些知识来减缓衰老和改善与年龄有关的疾病。