SIRT1 affects DNA methylation of polycomb group protein target genes, a hotspot of the epigenetic shift observed in ageing.

Background: SIRT1 is likely to play a role in the extension in healthspan induced by dietary restriction. Actions of SIRT1 are pleiotropic, and effects on healthspan may include effects on DNA methylation. Polycomb group protein target genes (PCGTs) are suppressed by epigenetic mechanisms in stem cells, partly through the actions of the polycomb repressive complexes (PRCs), and have been shown previously to correspond with loci particularly susceptible to age-related changes in DNA methylation.

Effects of Sirt1 on DNA methylation and expression of genes affected by dietary restriction.

Changes in DNA methylation across the life course may contribute to the ageing process. We hypothesised that some effects of dietary restriction to extend lifespan and/or mitigate against features of ageing result from changes in DNA methylation, so we determined if genes that respond to dietary restriction also show age-related changes in DNA methylation. In support of our hypothesis, the intersection of lists of genes compiled from published sources that (1) were differentially expressed in response to dietary restriction and (2) showed altered methylation with increased age was greater than expected.

The potential role of epigenetic responses to diet in ageing.

Epigenetic changes may be causal in the ageing process and may be influenced by diet, providing opportunities to improve health in later life. The aim of this review is to provide an overview of several areas of research relevant to this topic and to explore a hypothesis relating to a possible role of epigenetic effects, mediated by sirtuin 1, in the beneficial effects of dietary restriction, including increased lifespan. Epigenetic features of ageing include changes in DNA methylation, both globally and at specific loci, which differ between individuals.

Could Sirt1-mediated epigenetic effects contribute to the longevity response to dietary restriction and be mimicked by other dietary interventions?

Dietary restriction (DR) increases lifespan in a range of evolutionarily distinct species. The polyphenol resveratrol may be a dietary mimetic of some effects of DR. The pivotal role of the mammalian histone deacetylase (HDAC) Sirt1, and its homologue in other organisms, in mediating the effects of both DR and resveratrol on lifespan/ageing suggests it may be the common conduit through which these dietary interventions influence ageing.