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

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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.