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.

摘要 基因毒性应激是衰老的一个关键标志。有趣的是，与衰老研究密切相关的是核DNA 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、蛋白稳定、压力丧失 恢复力和细胞衰老。然而，基因毒性应激在哪里、何时以及如何驱动另一个 这些特征还没有被很好地理解。我们的总体前提是乙酰辅酶A代谢是调节 这些多重老化的标志和决定了衰老的轨迹。乙酰辅酶A是一种关键的代谢物 调节几个细胞过程，包括基因转录和蛋白质稳定性。乙酰辅酶A紧密结合在一起 在亚细胞池中调节，浓度或亚细胞通量的变化推动其数量变化 可用性和利用率。这个项目的目标是解决DNA损伤驱动的乙酰-辅酶A的作用 亚细胞定位和流量是衰老标志的“中枢”。我们假设(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的，也是充分的。我们将在多层中测试这一假设， 利用遗传、代谢和生化技术的创新组合，提供机械细节。缺乏 诱导生理相关DNA损伤的特定工具严重限制了我们理解 基因毒性应激与衰老的其他特征相联系。为了解决这个问题，我们创建了一个 化学遗传工具，以受控的方式诱导DNA氧化损伤。这一创新工具将使我们能够 为了直接测试DNA损伤是否改变了细胞自主或非细胞自主衰老的特征 举止。首先，我们将在多个细胞/组织中确定衰老标志的时间和等级 在正常寿命内，对DNA损伤的反应。此外，我们将确定一种关键的代谢作用 DNA损伤驱动的乙酰-辅酶A代谢重排中的酶，ATP-柠檬酸裂解酶ACLY。第二，我们将 乙酰辅酶A亚细胞池及其对衰老和衰老的贡献 联合分泌组(SASP)。使用计算工具构建统一的框架，我们将确定因果关系 这是个标志。这项工作在定量检测乙酰基的亚细胞调节方面具有技术创新。 CoA对DNA损伤的反应随年龄增长。这个项目对假设一部小说具有智力上的创新。 持续遗传毒性应激与亚细胞乙酰辅酶A代谢的关系。我们的分析，威尔 加深对DNA损伤诱导的乙酰-辅酶A代谢之间的联系的基本了解 和老化的特征，从而潜在地为针对共病和 老年人的多药联用。