Short‐term calorie restriction ameliorates genomewide, age‐related alterations inDNAmethylation

Abstract

SummaryDNA methylation plays major roles in many biological processes, including aging, carcinogenesis, and development. Analyses of DNA methylation using next-generation sequencing offer a new way to profile and compare methylomes across the genome in the context of aging. We explored genomewide DNA methylation and the effects of short-term calorie restriction (CR) on the methylome of aged rat kidney. Whole-genome methylation of kidney in young (6 months old), old (25 months old), and OCR (old with 4-week, short-term CR) rats was analyzed by methylated DNA immunoprecipitation and next-generation sequencing (MeDIP-Seq). CpG islands and repetitive regions were hypomethylated, but 5 0 -UTR, exon, and 3 0 -UTR hypermethylated in old and OCR rats. The methylation in the promoter and intron regions was decreased in old rats, but increased in OCR rats. Pathway enrichment analysis showed that the hypermethylated promoters in old rats were associated with degenerative phenotypes such as cancer and diabetes. The hypomethylated promoters in old rats related significantly to the chemokine signaling pathway. However, the pathways significantly enriched in old rats were not observed from the differentially methylated promoters in OCR rats. Thus, these findings suggest that short-term CR could partially ameliorate age-related methylation changes in promoters in old rats. From the epigenomic data, we propose that the hypermethylation found in the promoter regions of disease-related genes during aging may indicate increases in susceptibility to agerelated diseases. Therefore, the CR-induced epigenetic changes that ameliorate age-dependent aberrant methylation may be important to CR's health-and life-prolonging effects.

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

“…In support of such results, Hong et al reported that CR successfully suppressed immune response and increased lipid metabolism, thereby delaying aging and preventing age-associated diseases [83]. Kim et al also reported that CR implementation delayed age-associated alterations of DNA methylation, which could prevent the progression of age-related diseases [84].…”

Targeting chromatin aging - The epigenetic impact of longevity-associated interventions

“…number of age-associated degenerative phenotypes including cancer diabetes and inflammation (Kim et al, 2016). However, this study is not without its limitations.…”

Caloric restriction mitigates age-associated hippocampal differential CG and non-CG methylation

“…This study examined, for the first time, whether CR could prevent age-related changes in CNS DNA methylation, consistent with the concept that methylation is a potential molecular mechanism by which CR slows brain aging. CR has been reported outside of the CNS (liver, kidney, and blood) to prevent age-related CG methylation changes (Cole et al, 2017;Hahn et al, 2017;Kim et al, 2016;Maegawa et al, 2017) but has not been examined in the CNS.…”

“…Altered methylation at specific genomic locations is associated with the normal aging process (Wyss-Coray, 2016), and recent studies have shown a protective epigenetic effect of anti-aging interventions in the liver and kidney (Cole et al, 2017;Hahn et al, 2017;Kim et al, 2016). We previously described extensive age-related CG and non-CG methylation changes in the hippocampus of old mice (Masser et al, 2017), demonstrating that the DNA modification response to aging is different in the CNS as compared to other organs.…”