Title: Epigenetic responses to dietary change across organismal lifespan
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The epigenome is susceptible to changes during organismal lifespan. Some of these accumulate in a linear manner and appear to be intrinsically programmed (see Obj. 5), but additionally the epigenome responds to extrinsic and environmental factors amongst which diet has emerged as a key component. This objective focuses on epigenetic change as a function of age and diet during lifespan and at the interface between generations in a range of model organisms. Dietary restriction (DR) without malnutrition has beneficial health effects for model organisms as well as for humans, raising the prospect of preventative medicine against age-related disease. Understanding which aspects of normal metabolism are detrimental to health is key to the development of therapeutics that capture the beneficial effects of DR, in itself an unrealistic treatment. Various signalling pathways mediate the effects of DR on health, however, DR-associated epigenetic changes that likely mediate long-term consequences are largely unexplored. The effects of DR on lifespan are similar across disparate eukaryotes diverged by millions of years, allowing the use of genetically powerful model organisms including C. elegans and S. cerevisiae to elucidate underlying mechanisms. This allows us to approach the transcriptomic and metabolic consequences of DR in a systematic manner, and to probe the modulation of these effects by epigenetic states that change throughout life. A few histone modifiers have begun to emerge as conserved contributors to ageing, for example the histone acetyltransferase CBP-1/p300. In worms, CBP-1 mutants are short lived and gain no lifespan extension from DR; CBP expression is also predictive of lifespan in mice, and the closest functional CBP ortholog in yeast, Rtt109, is a critical regulator of lifespan30,31. H3K4 and H3K36 methylation have been similarly implicated in lifespan in multiple organisms32,33 but epigenetic changes linked to ageing in normal conditions and under DR largely remain unknown. In humans, the dramatic rise in average maternal age and BMI at pregnancy are both linked to an increased frequency of pregnancy complications as well as higher rates of developmental abnormalities and long-term disease predisposition even in the absence of chromosomal abnormalities34-36. The degree to which epigenetic deregulation contributes to these effects is not understood. Using the mouse as a model, we and others have demonstrated particularly tight control of epigenetic marks during reproduction and embryogenesis, including how gamete-derived DNA methylation persists through epigenetic reprogramming into the cleavage-stage embryo and has differential effects in the first lineages37. We can use this extensive knowledge to reference any maternal age-related changes and evaluate their likely functional outcomes. Although oocyte defects are a major component of the maternal age-associated reproductive decline, we also have strong evidence for an important contribution from the ageing maternal environment, through impacts on placentation and altered endometrial signals. In this Objective we will characterise age-linked epigenetic changes in a range of model systems, determine how these are modulated by diet and study downstream consequences for gene expression, lifespan, and reproductive health.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE