title: Age-related increase in levels of 5-hydroxymethylcytosine in mouse hippocampus is prevented by caloric restriction.
abstract: Aberrations in epigenetic marks have been associated with aging of the brain while caloric restriction (CR) and upregulation of endogenous antioxidants have been suggested as tools to attenuate the aging process. We have recently observed age-related increases in levels of 5-methylcytidine (5-mC) and DNA methyltransferase 3a (Dnmt3a) in the mouse hippocampus. Most of those age-related changes in these epigenetically relevant markers were prevented by CR but not by transgenic overexpression of the endogenous antioxidant superoxide dismutase 1 (SOD1). As recent work has suggested a distinct role for hydroxymethylation in epigenetic regulation of gene expression in the brain, the current study investigated age-related changes of 5-hydroxymethylcytosine (5-hmC) in the mouse hippocampus, and furthermore tested whether CR and transgenic upregulation of SOD1 affected any age-related changes in 5-hmC. Immunohistochemical analyses of 5-hmC in 12- and 24-month-old wild-type and transgenic mice overexpressing SOD1, which were kept under either a control or a calorie restricted diet, revealed an increase of 5-hmC immunoreactivity occurring with aging in the hippocampal dentate gyrus, CA3 and CA1-2 regions. Moreover, CR, but not overexpression of SOD1, prevented the age-related increase in the CA3 region. These findings indicate that the aging process in mice is connected with changes in epigenetic machinery in the hippocampus and suggest that CR acts by influencing epigenetic regulation.
authors.affiliation: School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Psychology, Faculty of Health, Medicine and Life Sciences, European Graduate School of Neuroscience (EURON), 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: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000367:Age Factors; D000818:Animals; D031204:Caloric Restriction; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D005786:Gene Expression Regulation / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D014018:Tissue Distribution
chemical_list: C000715535:Dnmt3a protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000090205:DNA Methyltransferase 3A