Spatial Acetyl-CoA metabolism as a regulator of Hallmarks of Aging

空间乙酰辅酶A代谢作为衰老标志的调节剂

• 批准号: 10901039
• 负责人: Aditi U Gurkar
• 金额: $ 38.66万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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/10901039
• 关键词: ATP Citrate (pro-S)-Lyase; Acetates; Acetyl Coenzyme A; Acute; Address; Affect; Age; Aging; Binding; Biochemical; Biochemical Reaction; Biological Aging; Caenorhabditis elegans; Cell Aging; Cell Nucleus; Cell physiology; Cells; Cessation of life; Chromatin; Coenzyme A; Communication; Computing Methodologies; Cytosol; DNA Damage; Data; Degenerative Disorder; Disease; Elderly; Enzymes; Epigenetic Process; Equilibrium; Gene Proteins; Generations; Genetic; Genetic Transcription; Genotoxic Stress; Goals; Health; Health Promotion; Histone Acetylation; Histones; Human; In Vitro; Intervention; Investigation; Life; Link; Longevity; Measurement; Membrane; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Nuclear; Organelles; Physiological; Polypharmacy; Process; Public Health; Regulation; Research; Rest; Role; Spatial Distribution; Stimulus; Stress; Supplementation; Techniques; Testing; Tissues; Work; age related; comorbidity; computerized tools; functional decline; genetic manipulation; healthy aging; improved; in vivo; innovation; insight; metabolomics; novel; novel therapeutic intervention; oxidative DNA damage; pharmacologic; prevent; protein aggregation; proteostasis; resilience; response; senescence; stress resilience; therapeutic target; tool

ABSTRACT Genotoxic stress is a key hallmark of aging. Interestingly, and of great relevance to aging research, nuclear DNA damage is inextricably linked to multiple aging hallmarks including: epigenetics, proteostasis, loss of stress resilience and cellular senescence. However, where, when and how does genotoxic stress drive the other hallmarks is not well-understood. Our overall premise is that acetyl-CoA metabolism is the ‘hub’ that regulates these multiple aging hallmarks and determines aging trajectories. Acetyl-CoA is a critical metabolite that modulates several cellular processes including the gene transcription and protein stability. Acetyl-CoA is tightly regulated in subcellular pools and a change in concentration or subcellular flux drives quantitative changes in its availability and utilization. The goal of this project is to address the role of DNA damage-driven acetyl-CoA subcellular localization and flux as the ‘hub’ of hallmarks of aging. We hypothesize that (1) generation and spatial distribution of acetyl-CoA are altered in response to DNA damage, and (2) rewiring of acetyl-CoA metabolism is necessary and sufficient to change aging trajectories. We will test this hypothesis in multi-layer, mechanistic detail using an innovative combination of genetic, metabolic and biochemical techniques. Lack of specific tools to induce physiologically relevant DNA damage has severely limited our ability to understand how genotoxic stress communicates with the rest of the hallmarks of aging. To address this, we created a chemoptogenetic tool to induce oxidative DNA damage in a controlled manner. This innovative tool will allow us to directly test whether DNA damage alters hallmarks of aging in a cell autonomous or non-cell autonomous manner. First, we will determine the timing and hierarchy among the hallmarks of aging in multiple cells/tissues across the normal lifespan, in response to DNA damage. In addition, we will determine the role of a key metabolic enzyme, ATP-citrate lyase ACLY in DNA damage-driven acetyl-CoA metabolic rewiring. Second, we will quantitatively dissect acetyl-CoA subcellular pools and their contribution to senescence and senescence associated secretome (SASP). Using computational tools to build a unified framework, we will identify causal hallmarks. This work is technically innovative for quantitatively examining the subcellular regulation of acetyl- CoA in response to DNA damage with age. This project is intellectually innovative for hypothesizing a novel relationship between persistent genotoxic stress and subcellular acetyl-CoA metabolism. Our analysis, will increase fundamental understanding of the connection between DNA damage-induced acetyl-CoA metabolism and aging hallmarks, thus potentially paving the way for new treatment strategies targeting co-morbidities and polypharmacy in the elderly.

抽象的 基因毒性应激是衰老的一个重要标志，与衰老研究、核DNA密切相关。 损伤与多种衰老特征有着千丝万缕的联系，包括：表观遗传学、蛋白质稳态、压力损失 然而，基因毒性应激在何时、何地以及如何驱动另一个因素。 我们的总体前提是乙酰辅酶A代谢是调节的“枢纽”。 这些多重衰老标志并决定了衰老轨迹。 紧密调节多种细胞过程，包括基因转录和蛋白质稳定性。 在亚细胞库中受到调节，浓度或亚细胞通量的变化会驱动其数量变化 该项目的目标是解决 DNA 损伤驱动的乙酰辅酶 A 的作用。 亚细胞定位和通量是衰老标志的“中心”，我们着迷于（1）世代和。 乙酰辅酶 A 的空间分布因 DNA 损伤而改变，以及 (2) 乙酰辅酶 A 的重新布线 新陈代谢对于改变衰老轨迹是必要且充分的，我们将在多个层面上检验这一假设。 缺乏使用遗传、代谢和生化技术的创新组合的机制细节。 诱导生理相关 DNA 损伤的特定工具严重限制了我们理解如何进行的能力 基因毒性压力与衰老的其他特征有关。为了解决这个问题，我们创建了一个模型。 化学光遗传学工具能够以受控方式诱导氧化 DNA 损伤。 直接测试 DNA 损伤是否会改变细胞自主或非细胞自主的衰老特征 首先，我们将确定多个细胞/组织的衰老标志之间的时间和层次。 在整个正常生命周期中，针对DNA损伤的反应，我们将确定一个关键代谢的作用。 DNA 损伤驱动的乙酰辅酶 A 代谢重连中的 ATP-柠檬酸裂解酶 ACLY 其次，我们将。 定量剖析乙酰辅酶A亚细胞池及其对衰老和衰老的贡献 使用计算工具构建统一的框架，我们将识别因果关系。 这项工作在定量研究乙酰基的亚细胞调节方面具有技术创新性。 CoA 响应随年龄增长的 DNA 损伤 该项目在智力上具有创新性，提出了一种新颖的假设。 我们的分析将持续性基因毒性应激与亚细胞乙酰辅酶A代谢之间的关系。 增加对 DNA 损伤诱导的乙酰辅酶 A 代谢之间联系的基本了解 和衰老特征，从而可能为针对共病和衰老的新治疗策略铺平道路 老年人的多重用药。