Location: Jean Mayer Human Nutrition Research Center On Aging
2018 Annual Report
Objectives
LAB NAME: Vitamin Metabolism & Aging
1. Develop new and efficient methods for assessing nutritional status in individuals for B vitamins and their functional markers with internal standards obtained from plants grown on D2O or yeast grown on C-13 glucose.
2. Determine the biochemical, pathological and functional impact of nutritional status and genetic variations in B complex vitamin metabolism with special emphasis on the effect of age, in human, animal and cell culture models. Consider the nutritional status of other B vitamins while studying the effect of each B vitamin.
3. Determine the impact of mandatory folic acid fortification of cereals including effects of improved nutritional status as well as excess intake of folic acid on outcomes including disease risk, cognitive function, inflammation and immune response, with emphasis on understanding the mechanism behind the side-effects.
Approach
LAB NAME: Vitamin Metabolism & Aging
We will use biochemical, molecular biological and epidemiological approaches to study the role of B vitamins and the genes involved in their metabolism, in modulating processes associated with aging, disease development and increased risk for diseases. We will explore the association between pyridoxal 5’-phosphate, the active form of vitamin B6 and inflammation by measuring the immunomodulatory compounds in plasma that are produced from pyridoxal 5’-phosphate-dependent reactions in a cohort of elders. Decrease in vitamin B12 status can potentially result in decrease in muscle strength. We will explore the association between vitamin B12 and muscle strength and power, to determine the feasibility of an intervention trial to improve muscle strength. Fortification of cereals with folic acid was adopted by the US and many other countries to reduce neural tube defects. While natural folate from plants and meat can enter the metabolic pathway directly, folic acid, the synthetic form of the vitamin in supplements and fortified foods, has to be reduced by dihydrofolate reductase prior to entering the metabolic pathway. A 19bp deletion polymorphism in intron 1 of dihydrofolate reductase has been associated with increased risk for cancer in supplement users. We will determine the effect of this 19bp deletion on gene expression and enzyme activity of dihydrofolate reductase and the reactions of folate pathway. Intake of folic acid in excess of the ability of the body to metabolize it has been associated with negative health outcomes. Using a mouse model we will determine the effect of excess intake of folic acid on immune function and response to infections. We will explore the association between the polymorphism in dihydrofolate reductase gene and folic acid intake in modulating the risk for breast cancer using the samples and data from the PLCO cohort.
Progress Report
Current evidence suggests that excess folate intake worsens the clinical and metabolic manifestations of vitamin B12 insufficiency, as indicated by the increase in the prevalence of anemia and cognitive dysfunction and plasma concentrations of homocysteine and methyl malonic acid (functional biomarkers of vitamin B12 which increase with deficiency). Our recent data show that polymorphisms in the vitamin B12 transport protein, transcobalamin, increase the risk for neuropathy in individuals with folate intake above 2xRDA, even when vitamin B12 intake is adequate. These adverse outcomes have been reported in older adults. The mechanism behind this association between excess folate and inadequate vitamin B12 is still not known. Development of adult rodent models of this interaction have been unsuccessful so far. There is now a vitamin B12 deficient model of Caenorhabditis elegans (C elegans). This model organism is also useful to study neurological consequences of vitamin B12 deficiency. Hence developing a C elegans model of excess folate under vitamin B12 deficiency can be used to study the mechanism behind the adverse effects of this nutrient imbalance in a cost- effective way. C elegans were grown on a diet of E coli grown in the absence of vitamin B12. Increasing concentrations of folic acid were provided to C elegans mixed with the bacterial lawn. We are now monitoring the effect of high dietary folic acid concentrations on C elegans by the following: 1) Concentration of homocysteine and methylmalonic acid, which are functional biomarkers of vitamin B12 status, and 2) Egg laying, which is a measure of neuronal response and memory 3) Life cycle and life expectancy.
Accomplishments
Review Publications
Sparks, J., Barbhaiya, M., Karlson, E.W., Ritter, S.Y., Raychaudhuri, S., Corrigan, C.C., Lu, F., Selhub, J., Chasman, D., Paynter, N.P., Ridker, P.M., Solomon, D.H. 2017. Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study. Arthritis and Rheumatism. 47(1):133-142. https://doi.org/10.1016/j.semarthrit.2017.02.003.
Ren, J., Murphy, G., Fan, J., Dawsey, S.M., Taylor, P.R., Selhub, J., Qiao, Y., Abnet, C.C. 2016. Prospective study of serum B vitamins levels and oesophageal and gastric cancers in China. Scientific Reports. 6:35281. https://doi.org/10.1038/srep35281.
McMahon, G.M., Hwang, S., Tanner, R.M., Jacques, P.F., Selhub, J., Muntner, P., Fox, C.S. 2015. The association between vitamin B12, albuminuria and reduced kidney function: an observational cohort study. BMC Nephrology. 16:7. https://doi.org/10.1186/1471-2369-16-7.
Miranti, E.H., Freedman, N.D., Weinstein, S.J., Abnet, C.C., Selhub, J., Murphy, G., Diaw, L., Mannisto, S., Taylor, P.R., Albanes, D., Stolzenberg-Solomon, R.Z. 2016. Prospective study of serum cysteine and cysteinylglycine and cancer of the head and neck, esophagus, and stomach in a cohort of male smokers. American Journal of Clinical Nutrition. https://doi.org/10.3945/ajcn.115.125799.
Sawaengsri, H., Bergethon, P., Qiu, W.Q., Scott, T.M., Jacques, P.F., Selhub, J., Paul, L. 2016. Transcobalamin 776C-->G polymorphism is associated with peripheral neuropathy in elderly with high folate intake. American Journal of Clinical Nutrition. https://doi.org/10.3945/ajcn.116.139030.
Mazumdar, M., Ibne Hasan, M., Hamid, R., Valeri, L., Paul Pottenplackel, L., Selhub, J., Rodrigues, E.G., Silva, F., Mia, S., Mostofa, M., Quamruzzaman, Q., Rahman, M., Christiani, D.C. 2015. Arsenic is associated with reduced effect of folic acid in myelomeningocele prevention: a case control study in Bangladesh. Environmental Health. 14:34. https://doi.org/10.1186/s12940-015-0020-0.
