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

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.