Working in yeast and human pluripotent stem cells (hPSCs), we shall establish whether modulating acetyl-CoA between acetylation and metabolism is a convergent mechanism to improve ageing health.

Metabolite cofactors for epigenetic modifying enzymes are highly conserved, making yeast an attractive system to dissect the impact of metabolites on epigenetic change during ageing. We have shown that metabolic alterations can alter the ageing trajectory of yeast cells: changing diet without caloric restriction or forcing an increase in respiration suppressed many phenotypes of ageing.

Obj. 1.1.1 Characterisation of acetyl-CoA biology in healthy ageing yeast.

Key questions involve (i) the fate of acetyl-CoA in healthy and unhealthy ageing, and (ii) the impact of acetyl-CoA on proteostasis.

Obj. 1.1.2 Optimising ACC1 modulation in mammalian cell change-of-state models.

To validate in human cells the regulatory interaction between AMPK and triacylglyceride synthesis through phosphorylation of ACC1. This will test in physiologically relevant cell types whether our yeast findings are translatable to human cells.

 

Deliverables

• Dataset linking metabolism, epigenetics and proteostasis in healthy and normal yeast ageing
• An ACC1-mutant hESC line for differentiation into diverse cell types