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；

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概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），两个标志衰老，与生理功能的丧失和与年龄相关的高级疾病的病因学有关。糖基化终末产物 (AGE) 是蛋白质糖基化负担增加的一个来源，是另一种情况的表现衰老的标志是蛋白质稳态的丧失，甲基乙二醛 (MGO) 是 AGE 的反应前体，会影响胰岛素抵抗 (IR) 和细胞衰老的病理生理学最近的一项研究表明 IR。加速 β 细胞衰老，导致胰腺组织功能下降和代谢状况恶化。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然而，当前的研究证实了这两种衰老特征的共存。在理解特征和影响之间的相互作用方面，我们的知识存在重大差距我们的长期目标是进一步研究这种新兴的现象。在组织特异性通讯的背景下，这是一个令人兴奋的研究领域，它决定了组织之间的相互作用本提案将具体提出以下关键问题：(a) 这三个特征如何？衰老的特征是相互影响的；(b) 是否存在任何组织特异性的层次结构和相互依赖性？不同组织中的三个特征之间的差异；(c) 可以采取多种干预措施来克服这些特征我们的中心假设是，MGO- 可以减缓衰老和与年龄相关的疾病。蛋白质诱导的糖化不仅作为 IR 和细胞衰老的内源驱动因素，而且还发挥着重要作用我们将测试脂肪组织和胰腺中这两个标志之间相互作用的关键作用。通过追求以下具体目标来提出假设：1）甲基乙二醛在诱导衰老中的作用 2) 甲基乙二醛在诱导 IR 中的作用；脂肪组织或胰腺 β 细胞通过蛋白质糖化释放胰岛素，3) 研究相互作用； MGO 诱导的蛋白质糖化 IR 与前脂肪细胞和原代 β 细胞之间的关系。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 来研究 MGO 在诱导组织特异性衰老和 IR 中的作用。确定衰老细胞在 MGO 诱导的 IR 中的重要性我们还将确定治疗潜力。结合一种新型的降糖鸡尾酒 Gly-Low，无论是否含有 senolytic，都会对在生理（高脂肪饮食）模型中改善 IR、衰老和寿命是这项工作的一个重要意义。正在帮助我们了解 MGO 诱导的蛋白质糖基化负荷、IR 和细胞之间的相互关系衰老，从而揭示这些特征在压力条件下如何相互作用如何利用这些知识来延缓衰老和改善与年龄相关的疾病。