Project 4. Maternal Diet, Epigenetics, and Lifespan
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.
Hypotheses & Aims
Project 4's central hypothesis is that maternal diet affects prenatal and
neonatal epigenetic characteristics through methylation of DNA cytosines to 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 Dnmt1 gene dosage and that some of these
changes will correlate with lifespan. Pregnant mice 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. Lifespan studies will assess the effects
of maternal diet or Dnmt1 gene 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.
Slide Presentation of Recent Data
Craig Cooney, Ph.D., Project Leader
Tatiana L Leaky, M.D., Research Assistant
Tonya M. Rafferty, Research Assistant
Dietrich J. Bell, Research Technician