It has become increasingly apparent that epigenetics, where the genome interacts with the environment, is central to our understanding of the relationship between aging and disease. DNA methylation is a key epigenetic mechanism controlling gene expression. Recent data suggest that there is a considerable epigenetic "drift" in aging, resulting in relative DNA hypomethylation in many tissues including T cells. The original RO1 was funded to examine the effect of aging on the epigenetic control of leukocyte chemokine system. We showed that aging is associated with increased T cell pro-inflammatory chemokine function that is at least in part controlled by DNA methylation. In this competing renewal, we will determine if the aging changes can be ameliorated by altering the T cell epigenome during the critical stages of immune system development. We hypothesize that the prenatal 'epigenetic environment'can modify T cell chemokine receptor response that will in turn determine the late-life susceptibility to chronic inflammatory diseases.
Specific Aim 1 will determine the effect of a pre-natal methyl-donor supplementation diet on murine T cell chemokine function throughout the life span.
Specific Aim 2 will assess the consequence of diet-induced epigenetic changes on the onset and progression of coronary artery disease.
The mechanistic link between aging and chronic diseases in the elderly is poorly understood. Using mouse models, the proposal will examine the effect of a pre-natal methyl-donor supplementation diet on the onset and progression of coronary artery disease in late life.
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