The diet dilemma: can you eat what you like and live happily ever after?

Theme: Bioscience for Health

The discovery that ageing can be slowed by dietary intervention raises the prospect of extending lifespan and healthspan through lifestyle change or long-term drug treatment. Dietary restriction (DR) without malnutrition has beneficial health effects for model organisms as well as humans but forms an unattractive lifestyle choice. Finding more palatable alternatives to DR requires a better understanding of why and how organisms respond to food. It is widely (and mistakenly) assumed that DR simply slows down metabolism leading directly to an increase in lifespan. Remarkably, we have recently shown that in yeast, a classic model organism for ageing that responds well to DR, simply changing but not restricting diet dramatically improves health-span, such that cells actually became fitter with age prior to death at a normal age! This means that life-span and health can be separated, so ageing cannot be the inevitable decline towards death that we culturally perceive. In fact lifespan extension by DR requires chromatin modifying enzymes, at least in lower eukaryotes, suggesting that DR instigates an epigenetic reprogramming event, leading to altered gene expression patterns that increase lifespan and promote healthy ageing. We aim to determine the nature of these gene expression changes and how they positively impact the ageing cell.

Various signalling pathways mediate the effects of DR, however, the epigenetic changes associated with DR that likely mediate long-term consequences are vastly unexplored. In consequence, considerable debate surrounds the
mechanism of long term DR action, not helped by the fact that lifespan itself is an inaccurate and pleotropic reporter. Using a direct readout through transcriptomics should facilitate dissection of the multiple overlapping epigenetic
mechanisms that clearly potentiate DR. DR alters lifespan in remarkably similar ways across eukaryotes diverged by millions of years, allowing the use of genetically powerful model organisms such as yeast to elucidate underlying
mechanisms.

Our lab has developed improved methods for transcriptomic and chromatin analysis in ageing yeast, and discovered clear impacts of histone modification on the ageing transcriptome. This project will initially define the transcriptomic changes associated with ageing under various DR regimens. It will then examine the importance of histone modifications in mediating short and long-term consequences of DR using a range of histone modification mutants including acetyltransferases, methyltransferases and deacetylases with known roles in gene expression regulation or ageing phenotypes. Selected mutants that impair DR-mediated gene expression change will be used to assess the fitness trade-off between short-term food utilization and longevity. Finally, based on these studies, experiments will be designed to reconstitute the long term epigenetic changes mediated by DR.

Techniques: Yeast genetics and ageing cell purification; RNAseq, ChIPseq and bioinformatics.
ENWW: Data driven biology