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。虽然热量限制增加了寿命并改善了衰老健康，但现在可以剖析这两种结果并确定不太严重的干预措施，因为研究表明，改变代谢状态，而不是最低能量摄入，这是推动有益结果的原因。现有的抗衰老疗法和干预措施取得了一定的成功，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学降到最低。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，Houseley实验室发现了一种非限制性的饮食干预，似乎可以促进酵母的健康老化。在这个项目中，我正在探索这种反应背后的代谢成分，通过检查驱动衰老结果的代谢物通量的变化。使用Houseley实验室开创的老化方法，我发现了一种由AMPK介导的机制，AMPK是一种中央代谢调节因子，它可以解除营养感应并促进乙酰辅酶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，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。

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.