title: Prevention of age-related changes in hippocampal levels of 5-methylcytidine by caloric restriction.
abstract: Aberrant DNA methylation patterns have been linked to molecular and cellular alterations in the aging brain. Caloric restriction (CR) and upregulation of antioxidants have been proposed as interventions to prevent or delay age-related brain pathology. Previously, we have shown in large cohorts of aging mice, that age-related increases in DNA methyltransferase 3a (Dnmt3a) immunoreactivity in the mouse hippocampus were attenuated by CR, but not by overexpression of superoxide dismutase 1 (SOD1). Here, we investigated age-related alterations of 5-methylcytidine (5-mC), a marker of DNA methylation levels, in a hippocampal subregion-specific manner. Examination of 5-mC immunoreactivity in 12- and 24-month-old wild type (WT) mice on control diet, mice overexpressing SOD1 on control diet, wild type mice on CR, and SOD1 mice on CR, indicated an age-related increase in 5-mC immunoreactivity in the hippocampal dentate gyrus, CA3, and CA1-2 regions, which was prevented by CR but not by SOD1 overexpression. Moreover, positive correlations between 5-mC and Dnmt3a immunoreactivity were observed in the CA3 and CA1-2. These findings suggest a crucial role for DNA methylation in hippocampal aging and in the mediation of the beneficial effects of CR on aging.
authors.affiliation: School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, European Graduate School of Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Chouliaras
authors.forename: Daniel L A
authors.initials: DL
authors.lastname: van den Hove
authors.forename: Gunter
authors.initials: G
authors.lastname: Kenis
authors.forename: Stella
authors.initials: S
authors.lastname: Keitel
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Hof
authors.forename: Jim
authors.initials: J
authors.lastname: van Os
authors.forename: Harry W M
authors.initials: HW
authors.lastname: Steinbusch
authors.forename: Christoph
authors.initials: C
authors.lastname: Schmitz
authors.forename: Bart P F
authors.initials: BP
authors.lastname: Rutten
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D031204:Caloric Restriction / Q000379:methods*; D003562:Cytidine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: C000715535:Dnmt3a protein, mouse; D003562:Cytidine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000090205:DNA Methyltransferase 3A; C016568:5-methylcytidine