1a. Objectives (from AD-416)
1. Determine the impact of mandatory food folic acid fortification in the United States. 2. Determine the interrelationships between B vitamin status, methionine intake, genetic polymorphism and plasma homocysteine. 3. Determine the hereditary association of plasma homocysteine and vitamin status. 4. Determine the biochemical, pathological and functional impact of nutritional and genetic disruptions of one-carbon metabolism, in animal models of age-related vascular and neurological dysfunction, with emphasis on the roles of B vitamins, homocysteine and methionine in tissue-specific susceptibility to disease.
1b. Approach (from AD-416)
In this project, we will use multiple approaches to study the biochemistry and molecular biology of the interaction of B vitamins with each other and their role in modulating the risk for age-related pathologies, and the genetic factors that influence these interactions. We will determine the interaction between vitamin B12 status, unmetabolized folic acid, methyl tetrahydrofolate and folic acid intake in relation to cognitive impairment, bone mineral density, cardiovascular disease risk, diabetes and cancer. For this purpose, we will measure the unmetabolized folic acid and methyl folate in the plasma of participants in National Health and Nutrition Examination Survey 1999-2002 and Framingham Heart Study (FHS) Offspring cohorts, measure plasma concentration of methylmalonic acid (MMA) in FHS Offspring cycle 7 examinations and use plasma MMA as a marker of vitamin B12 status. We will also use an animal model of vitamin B12 deficiency to characterize the biochemical and hematological effect of high folate status under vitamin B12 deficiency. The gene-nutrient interaction between folate and the 677C>T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene will be studied by determining the changes in DNA methylation and gene expression using microarray analysis after a 3-month dietary supplementation of 400µg/day folic acid in individuals homozygous for the C and T alleles of the MTHFR polymorphism. The heritability of plasma homocysteine concentration in FHS cohort will be determined by comparing data on plasma homocysteine from 3 generations of FHS participants in the context of their plasma folate and vitamin B12 status, and by determining the association between polymorphisms in genes that influence methylation of homocysteine including those involved in uptake of vitamin B12, and plasma homocysteine concentration.
3. Progress Report
This project includes the work of a project at the HNRCA funded through a Specific Cooperative Agreement with Tufts University. For further information and progress report, see 1950-51520-011-01S, The Role of B Vitamins and One Carbon Metabolism in Aging.
1. High folic acid levels are related to anemia and poor cognitive test results in seniors. Folic acid from diet and supplements has to be converted into a biologically active form. High folic acid intake may result in presence of biologically inactive unutilized folic acid in the body. ARS-funded researchers from Tufts University in Boston, MA have found that presence of unutilized folic acid in blood is related to anemia and poor cognitive test performance in American seniors. Presence of unutilized folic acid in blood was also related to increased occurrence of anemia in alcohol users. In seniors with a low vitamin B12 nutritional status, the presence of unutilized folic acid in blood was related to lower cognition. When vitamin B12 nutritional status is low, higher level of biologically active folate in the blood was related to increased odds of anemia. The results of this study show that nutritional imbalance due to high intake of folic acid can have negative health consequences especially when there is deficiency of vitamin B12.
2. Higher intake of vitamin B-6 may protect against inflammation. Low blood levels of the active form of vitamin B6 (PLP) have been linked to inflammation and the occurrence of inflammatory diseases like cardiovascular disease, rheumatoid arthritis and diabetes (Vitamin Metabolism Lab). However, the implications of these findings are unclear. ARS-funded researchers from Tufts University in Boston, MA have found that vitamin B-6 intake from diet and vitamin supplements is inversely related to inflammation status. We investigated the relationship between PLP and a marker of inflammation C-reactive protein (CRP) in participants of National Health and Nutrition Examination Survey which samples the general U.S. population. The results showed that higher vitamin B-6 intakes were linked to protection against inflammation. The results identify low B6 intake as a possible risk factor for inflammatory disease.