Re-wiring the metabolic regulatory system to promote a healthy ageing trajectory

重新连接代谢调节系统以促进健康的衰老轨迹

• 批准号: EP/Y027892/1
• 负责人: Hanane Hadj-Moussa
• 金额: $ 25.55万
• 依托单位: Babraham Institute
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY027892%2F1
• 关键词: Re; wiring; metabolic; regulatory; system

Ageing is a seemingly inevitable part of life, and yet, a wealth of research has shown that environmental circumstances can drive cells into different ageing trajectories. While caloric restriction increases lifespan and improves ageing health, dissecting these two outcomes, and identifying less severe interventions is now possible as studies have shown that it is altered metabolic states, not minimal energy intake that is driving beneficial outcome. The anti-ageing therapeutics and interventions that exist are marginally successful, and this is likely because we have yet to fully understand what happens when cells age and how this pathology can be minimized. The crux of my research is understanding the metabolic and diet-based drivers that can extend healthspan, the portion of life free of morbidity and pathology, by altering metabolic states without undergoing severe dietary restriction. Recently, the Houseley lab has uncovered a nonrestricted dietary intervention that appears to promote healthy ageing in yeast. In this project, I am exploring the metabolic components underlying this response by examining changes in metabolite flux that drive ageing outcomes. Using the ageing methods pioneered in the Houseley lab, I have discovered a mechanism mediated by AMPK, a central metabolic regulator, that uncouples nutrient-sensing and facilitates rapid turnover of Acetyl-Coenzyme A into lipid metabolism, rather than into age-dependent transcriptional dysregulation. This project will benefit from my experience in metabolic reprogramming, expertise at the Babraham Institute, and a combination of powerful molecular approaches (mass spectrometry, transcriptomics, flow cytometry). This work has the potential to transform our understanding of how ageing pathology arises, provide new leads for developing dietary and pharmacological interventions for healthy ageing, and is an excellent training opportunity that will prepare me for scientific independence.

衰老似乎是生命中不可避免的一部分，然而，大量的研究表明，环境条件可以驱使细胞进入不同的衰老轨迹。虽然热量限制可以延长寿命，改善老龄化健康，但研究表明，是代谢状态的改变，而不是最小的能量摄入，推动了有益的结果，因此，分析这两种结果，并确定不那么严重的干预措施，现在是可能的。现有的抗衰老疗法和干预措施收效甚微，这可能是因为我们还没有完全了解细胞衰老时会发生什么，以及如何将这种病理降到最低。我研究的关键是了解代谢和饮食驱动因素，这些因素可以通过改变代谢状态而不进行严格的饮食限制来延长健康寿命，即没有发病和病理的生命部分。最近，豪斯利实验室发现了一种非限制性饮食干预，似乎可以促进酵母的健康老化。在这个项目中，我通过研究驱动衰老结果的代谢物通量的变化来探索这种反应背后的代谢成分。利用Houseley实验室开创的衰老方法，我发现了一种由AMPK介导的机制，AMPK是一种中枢代谢调节剂，可以解除营养感应的耦合，促进乙酰辅酶a快速转化为脂质代谢，而不是转化为年龄依赖性转录失调。这个项目将受益于我在代谢重编程方面的经验，在Babraham研究所的专业知识，以及强大的分子方法（质谱，转录组学，流式细胞术）的结合。这项工作有可能改变我们对衰老病理如何产生的理解，为发展健康老龄化的饮食和药物干预提供新的线索，并且是一个很好的培训机会，将为我的科学独立做好准备。