title: Short term methionine restriction increases hepatic global DNA methylation in adult but not young male C57BL/6J mice.
abstract: Despite well-documented evidence for lifespan extension by methionine restriction (MR), underlying mechanisms remain unknown. As methionine can alter S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), the substrate and product of DNA methyltransferase-1 (DNMT1), we hypothesized that MR diet alters DNA methylation. Young (8-week-old) and adult (1-year-old) male C57BL/6J mice were fed diets with different levels of methionine (0.12%-MR, 0.84%-CD) for 12weeks. Functional indicators of DNA methylation, including global methylation (GM), gene-specific methylation (GSM) and LINE-1 methylation; and biochemical factors affecting DNA methylation, SAH, SAM, and DNMT1 were assessed in different tissues. MR altered DNA methylation depending on the age of intervention. While MR had no effect on hepatic GM in young animals, it increased GM by 27% over CD in adults (p<0.01). In comparison with young animals, hepatic GM levels were 17% lower in CD adults (p<0.05), but not different in MR adults. The MR-induced increase in hepatic GM was associated with a 38% decrease in SAH levels in adults (p<0.001), with SAH and GM levels being negatively correlated (r2=0.33, p<0.001). No changes were observed in DNMT protein levels in liver. In adipose tissue, MR caused a 6% decline in GM in adults (p<0.05), a corresponding 2-fold increase in SAH (p<0.05), and a 2-fold decrease in DNMT1 (p<0.01). MR caused both increases and decreases in GSM of liver and adipose. No changes were observed in LINE-1. Together, these findings provide evidence for protective effects of MR diet on hepatic DNA hypomethylation in adults, apparently mediated by SAH. These findings also indicate that altered DNA methylation might be playing a role in benefits conferred by MR diet.
authors.affiliation: Orentreich Foundation for the Advancement of Science, Animal Science Laboratory, Cold Spring-on-Hudson, NY 10516, USA.
authors.forename: Dwight A L
authors.initials: DA
authors.lastname: Mattocks
authors.affiliation: Duke University School of Medicine, Department of Pharmacology and Cancer Biology, Durham, NC 27710, USA.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Mentch
authors.affiliation: Orentreich Foundation for the Advancement of Science, Animal Science Laboratory, Cold Spring-on-Hudson, NY 10516, USA.
authors.forename: Jelena
authors.initials: J
authors.lastname: Shneyder
authors.affiliation: Orentreich Foundation for the Advancement of Science, Animal Science Laboratory, Cold Spring-on-Hudson, NY 10516, USA.
authors.forename: Gene P
authors.initials: GP
authors.lastname: Ables
authors.affiliation: Penn State College of Medicine, Department of Pharmacology, Mass Spectrometry Core Facility, Hershey, PA 17033, USA.
authors.forename: Dongxiao
authors.initials: D
authors.lastname: Sun
authors.affiliation: Penn State College of Medicine, Department of Public Health Sciences, Hershey, PA 17033, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Richie
authors.affiliation: Duke University School of Medicine, Department of Pharmacology and Cancer Biology, Durham, NC 27710, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Locasale
authors.affiliation: Orentreich Foundation for the Advancement of Science, Animal Science Laboratory, Cold Spring-on-Hudson, NY 10516, USA. Electronic address: snichenametla@orentreich.org.
authors.forename: Sailendra N
authors.initials: SN
authors.lastname: Nichenametla
mesh_terms: D000375:Aging; D000818:Animals; D031204:Caloric Restriction; D019175:DNA Methylation / Q000187:drug effects*; D004032:Diet; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013997:Time Factors
chemical_list: D008715:Methionine
keywords: Aging; Caloric restriction; DNA methylation; Methionine; One-carbon cycle; Sulfur amino acids