Enzymatic methylation of DNA to form 5-methyldeoxycytidine (5MdC) is essential to mammalian development and adult health. In mice, some effects of 5MdC include diverse epigenetic phenotypes which can markedly affect adult health and survival. Maternal diet can change both epigenetic phenotype and 5MdC pattern of offspring although the effects of maternal diet on the health and lifespan of these offspring have not been determined. The central hypothesis of this proposal is that maternal diet affects prenatal and neonatal epigenetic characteristics through 5MdC and will thereby affect the adult lifespan of offspring. 5MdC and lifespan will also be studied in mice with only one copy of the DNA methyltransferase 1 gene (Dnmt1). Additionally, it is proposed that some specific changes in metabolism, gene expression, and 5MdC pattern will be effected by maternal diet or Dnmtl gene dosage and that some of these changes will correlate with lifespan. Pregnant ]nice will be fed methyl-supplemented or control diets, or will be bred with only one copy of Dnmt1 and numerous biological and molecular assays will be done on the offspring. Broad metabolite and gene expression assays will also be made on pregnant mothers. Lifcspan studies will assess the effects of maternal diet or Dnmt1 gone dosage on median and maximum lifespan of offspring. Cross-sectional studies will attempt to determine underlying mechanisms of aging affected by maternal diet and by Dnmt1 gene dosage. Determinations of longevity, metabolism, methylation, and gene expression will compare progeny that are genetically normal, genetically mutant at the agouti locus but phenotypically normal due to gene silencing by 5MdC, and phenotypically abnormal due to expression of the mutant agouti gene. The work proposed herein has the potential to establish a means and mechanism whereby a maternal dietary supplement or reduction in Dnmt1 gone dosage can improve the lifelong health and lifespan of offspring. This work also has the potential to identify nutrients, metabolites, genes and 5MdC that contribute to the epigenetic modulation of longevity. The application of such findings in humans could lead to improved maternal nutritional balances, or adult DNMT manipulation, to improve health and lifespan.
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