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

Abstract

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. We also hypothesised that some effects of Sirt1, which may play a pivotal role in beneficial effects of dietary restriction, are mediated through DNA methylation. We thus measured effects of Sirt1 overexpression and knockdown in a human cell line on DNA methylation and expression of a panel of eight genes that respond to dietary restriction and show altered methylation with age. Six genes were affected at the level of DNA methylation, and for six expressions were affected. In further support of our hypothesis, we observed by DNA microarray analysis that genes showing differential expression in response to Sirt1 knockdown were over-represented in the complied list of genes that respond to dietary restriction. The findings reveal that

Metabolic programming of a beige adipocyte phenotype by genistein

“…Cell lysates were prepared and protein concentration was measured as described above. SDS‐PAGE, transfer of proteins to PVDF membrane and probing with primary and secondary antibodies to detect Sirt1 and α‐tubulin were as described previously . Signals for Sirt1 and α‐tubulin were measured using Odyssey software, as described previously , and data were expressed as a ratio, which was then normalized to control.…”

Aging and DNA methylation

“…Not only one-carbon metabolism-related processes lead to global hypomethylation: global hypomethylation can also occur via a peroxisome proliferator-induced mechanism [ 74 ]. Also, there are some hints based on cell culture experiments that altered DNA methylation events are correlated to Sirt1 expression levels, which may play a pivotal role in the beneficial effects of dietary restriction, which itself is believed to extend lifespan [ 75 ]. The enzymes, which transfer a methyl group from SAM to DNA producing 5-methylcytosine, are the family of DNA methyltransferases (DNMTs) that include DNMT1, DNMT3A, DNM3B and DNMT3L [ 76 ].…”

DNA Methylation Changes are Associated with the Programming of White Adipose Tissue Browning Features by Resveratrol and Nicotinamide Riboside Neonatal Supplementations in Mice

“…A possibility could involve the NAD + -dependent protein deacetylase sirtuin 1 (SIRT1). RSV and NR are both described as activators of SIRT1 (though through different mechanisms) [51,56,57], and SIRT1 has epigenetic activity, as it impacts global and gene-specific DNA methylation [58][59][60] and interacts with and deacetylates components of the DNA methylation machinery [60][61][62]. Still, RSV and NR have additional, non-overlapping biological targets for interaction besides SIRT1, and in fact, it is to be noted that effects of neonatal RSV and NR treatments observed in our previous studies [6,8] and in this work are similar, but not identical.…”