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

衰老似乎是生命中不可避免的一部分，然而，大量研究表明，环境环境可以推动细胞进入不同的衰老轨迹。虽然卡路里限制延长了寿命并改善了老龄化健康，但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，因为研究表明，推动有益结果的是代谢状态的改变，而不是最低的能量摄入量。现有的抗衰老疗法和干预措施略有成功，这可能是因为我们还没有完全了解细胞老化时会发生什么，以及如何将这种病理降至最低。我的研究的关键是了解代谢和基于饮食的驱动因素，这些因素可以通过改变代谢状态而不经历严格的饮食限制来延长健康寿命，即没有疾病和病理的那部分生活。最近，豪斯利实验室发现了一种无限制的饮食干预措施，似乎可以促进酵母中的健康衰老。在这个项目中，我正在通过检测推动衰老结果的代谢物流量的变化来探索这种反应背后的代谢成分。使用Houseley实验室首创的衰老方法，我发现了一种由中央代谢调节因子AMPK介导的机制，该机制使营养感知解偶联，并促进乙酰辅酶A快速转化为脂质代谢，而不是年龄相关的转录失调。这个项目将受益于我在代谢重新编程方面的经验，在巴普拉姆研究所的专业知识，以及强大的分子方法(质谱学、转录组分、流式细胞术)的组合。这项工作有可能改变我们对衰老病理学如何产生的理解，为开发健康老龄化的饮食和药物干预措施提供新的线索，并是一个极好的培训机会，将使我为科学独立做好准备。

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.