Under construction
Caloric restriction remains the most effective intervention against ageing, but it is unrealistic as a societal intervention to improve ageing health. Unfortunately, just as we do not understand the mechanism of ageing, we similarly do not understand how or why caloric restriction works. We study the ageing process in budding yeast (yes, ageing occurs in yeast and looks surprisingly like ageing in us!) to discover how caloric restriction works and to re-wire yeast metabolism to gain similar benefits on a normal, unrestricted diet.
We have shown that restricting the diet of yeast is not the only way to prevent them senescing (losing fitness before they die), and changing diet dramatically improves healthspan.
Figure
So by changing our yeast onto an unlimited galactose diet we find that cells can remain fit and healthy right to the end of life. Unexpectedly, this does not extend lifespan which means that becoming progressively more sick before death is not an intrinsic part of the ageing process. In other words, healthspan and lifespan are separable.
by Horkai et al
But galactose-rich food is unlikely to be the answer for us!
So we have dissected the metabolic deficiencies that lead to fitness loss when yeast age on a normal rich, high glucose diet. These are remarkably simple:
- A failure to produce sufficient fatty acids
- An accumulation of the fatty acid precursor acetyl coenzyme A
We have then created a mutant called A2A which remains fit to the end of life even on a rich, high glucose diet.
Data figure
A2A has two parts:
- Increased activity of the nutrient sensing kinase AMPK
- A modified version of the fatty acid synthesis enzyme Acetyl coenzyme A carboxylase (ACC) that is not inhibited by AMPK
Together these mutations ensure that cells make sufficient fatty acids, and that any excess acetyl coenzyme A is burnt in the mitochondria.
by Hadj-Moussa et al.
What is really exciting about this is that AMPK and ACC are conserved throughout eukaryotes, and we are currently testing whether this A2A system improves ageing health and responses to diet in flies and in mice.