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; 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 遗传毒性应激是衰老的关键标志。有趣的是，核DNA与衰老研究非常相关 损害与多个衰老标志有着千丝万缕的联系 弹性和细胞感应。但是，遗传毒性应力在哪里，何时以及如何驱动另一个 标志并不理解。我们的总体前提是，乙酰-COA代谢是调节的“枢纽” 这些多个老化的标志并决定了衰老轨迹。乙酰辅酶A是一种关键的代谢产物 调节几个细胞过程，包括基因转录和蛋白质稳定性。乙酰-COA紧密 在亚细胞池中调节和浓度或亚细胞滤光片的变化驱动其定量变化 可用性和利用率。该项目的目的是解决DNA损伤驱动的乙酰辅酶A的作用 亚细胞定位和通量作为衰老标志的“枢纽”。我们假设（1）一代和 乙酰辅酶A的空间分布因DNA损伤而改变，（2）乙酰辅酶A 代谢是必要的，足以改变衰老轨迹。我们将在多层中检验该假设， 使用遗传，代谢和生化技术的创新组合的机械细节。缺乏 诱导身体相关的DNA损伤的特定工具严重限制了我们了解如何了解的能力 遗传毒性应激与衰老的其余标志交流。为了解决这个问题，我们创建了一个 化学发生工具以受控方式诱导氧化DNA损伤。这种创新的工具将使我们 直接测试DNA损伤是否会改变细胞自主或非电池自主的衰老标志 方式。首先，我们将确定多个细胞/组织中衰老标志的时间和层次结构 在正常的寿命中，响应DNA损伤。此外，我们将确定关键代谢的作用 DNA损伤驱动的乙酰-COA代谢重新布线中的酶，ATP-citrate裂解酶Acly。第二，我们会的 定量剖析乙酰辅酶A亚细胞池及其对感应和敏感的贡献 相关的分泌组（SASP）。使用计算工具来构建统一的框架，我们将确定催化 标志。这项工作在技术上具有创新性，用于定量检查乙酰基的亚细胞调节 COA响应DNA损伤随着年龄的增长。该项目对假设小说具有智能创新性 持续的遗传毒性应激与亚细胞乙酰辅酶A代谢之间的关系。我们的分析，意志 增加对DNA损伤诱导的乙酰-COA代谢之间联系的基本了解 和老化的标志，因此有可能为针对合并症和的新疗法铺平道路 较早的多剂。