Gail P. A. Kauwell

Folate: A key to optimizing health and reducing disease risk in the elderly

Inadequate folate status is associated with an increased risk for chronic diseases that may have a negative impact on the health of the aging population. Folate, a water-soluble vitamin, includes naturally occurring food folate and synthetic folic acid in supplements and fortified foods. Inadequate folate status may result in hyperhomocysteinemia, a significant risk factor for atherosclerotic vascular disease, changes in DNA that may result in pro-carcinogenic effects and increased risk for cognitive dysfunction. Folate status may be negatively influenced by inadequate intake, genetic polymorphisms and interactions with various drugs. In the US, folic acid is now added to enriched grain products and continues to be included in the majority of ready-to-eat breakfast cereals. Recent data indicate that the folate status in the US population has improved significantly, presumably due to the effects of fortification. Folic acid (not food folate) intake in excess of the Tolerable Upper Intake Level may mask the diagnosis of a vitamin B12 deficiency, which is more prevalent in the elderly than younger individuals. When folic acid supplements are recommended, a multivitamin that includes vitamin B12 should also be advised. To safely and effectively increase folate intake in the elderly, naturally occurring folate-rich food sources should be promoted. Folate-rich foods include orange juice, dark green leafy vegetables, asparagus, strawberries and legumes. These foods are also excellent sources of other health-promoting nutrients associated with chronic disease risk reduction.

Relationship of Folate to Colorectal and Cervical Cancer: Review and Recommendations for Practitioners

Evidence suggests that folate may play a role in cancer prevention. A plausible mechanism for prevention lies in the integral role that folate plays in deoxyribonucleic acid (DNA) synthesis and methylation. DNA methylation most likely regulates gene expression. Abnormal methylation, specifically hypomethylation, has been associated with tumorigenesis. The availability of methyl groups needed for adequate DNA methylation may be negatively influenced by low folate status, alcohol intake, or genetic polymorphisms that affect folate metabolism. Observational studies evaluating the association between folate and risk for colorectal and cervical cancers or precancerous conditions have produced conflicting results, and clinical trial data are needed to confirm a cause-and-effect relationship. However, several studies show interesting associations between cancer risk and factors that influence methyl group availability. Although data relating folate to cancer risk remain equivocal, when coupled with the other potential health benefits associated with folate, evidence supports recommending that people consume folate-rich foods such as fruits and vegetables. People consuming alcohol on a daily basis may especially benefit from additional folate in their diets.

Daily intake of 4 to 7 μg dietary vitamin B-12 is associated with steady concentrations of vitamin B-12–related biomarkers in a healthy young population

BACKGROUND Studies have questioned whether the current Recommended Dietary Allowance (RDA) of 2.4 microg vitamin B-12/d is adequate. OBJECTIVE We examined the association between dietary vitamin B-12 intake and biomarkers of vitamin B-12 status. DESIGN Dietary vitamin B-12 intake was estimated, and biomarkers of vitamin B-12 status were measured, in healthy men and women (n = 299; age range: 18-50 y) who were recruited from a Florida community. The National Cancer Institute Diet History Questionnaire was used. Plasma cobalamin, total transcobalamin, holo-transcobalamin, methylmalonic acid (MMA), total homocysteine (tHcy), and autoantibodies against intrinsic factor (IF) and Helicobacter pylori were analyzed in blood samples. RESULTS Antibodies to H. pylori were detected in 12% of subjects (35/299), and negative results for IF antibodies were obtained for all subjects. The intake of vitamin B-12 correlated significantly with cobalamin, holo-transcobalamin, MMA, and tHcy. Subjects were divided into quintiles on the basis of their dietary vitamin B-12 intake (range: 0.42-22.7 microg/d), and biomarkers of vitamin B-12 status were plotted against estimated dietary vitamin B-12 intake. All biomarkers appeared to level off at a daily dietary vitamin B-12 intake between 4.2 and 7.0 microg. CONCLUSION In persons with normal absorption, our data indicate that an intake of 4-7 microg vitamin B-12/d is associated with an adequate vitamin B-12 status, which suggests that the current RDA of 2.4 microg vitamin B-12/d might be inadequate for optimal biomarker status even in a healthy population between 18 and 50 y of age.

Plasma homocyst(e)ine concentrations in pregnant and nonpregnant women with controlled folate intake.

Objective To assess the effects of folate intake and pregnancy on plasma total homocyst(e)ine concentrations in women during the second trimester of pregnancy compared with young, healthy nonpregnant women. Methods The diet provided either 450 or 850 μg of folate per day. These levels are approximately the current (400 μg/day) and previous (800 μg/day) Recommended Dietary Allowances for folate in pregnant women. Folate was provided as both food folate (120 μg/day) and supplemental folic acid (either 330 or 730 μg/day) for a period of 12 weeks. Plasma homocyst(e)ine (sum of free and protein-bound homocysteine), serum folate, and erythrocyte folate concentrations were determined weekly. Results Homocyst(e)ine concentrations were lower in pregnant women during the second trimester of normal pregnancy than in nonpregnant controls, independent of dietary folate intake. The overall mean (± standard deviation) homocyst(e)ine concentration of the pregnant subjects (5.4 ± 1.4 μmol/L) was significantly lower than that observed in the nonpregnant control group (8.7 ± 1.7 μmol/L) (P < .0001). This difference in homocyst(e)ine concentrations remained constant throughout the 12 weeks of the investigation. Conclusion The folate intakes in this investigation were adequate to maintain constant homocyst(e)ine concentrations in pregnant and nonpregnant women. The lower homocyst(e)ine concentrations observed in pregnant subjects compared with nonpregnant controls may be a physiologic response to pregnancy.

Obesity affects short-term folate pharmacokinetics in women of childbearing age.

Maternal folate status and body mass index (BMI) are independent risk factors for neural tube defects (NTD). Population-based studies have identified an inverse association between serum folate and BMI, after adjusting for intake. The objective of this intervention study was to compare the relationship between BMI and the short-term pharmacokinetic response to an oral dose of folic acid. Healthy obese (BMI ⩾30.0 kg m−2; n=16) and normal-weight (BMI 18.5–24.9 kg m−2; n=16) women of childbearing age (18–35 years) were administered a single oral dose of folic acid (400 μg). Blood samples were collected over a 10-h period to evaluate the serum folate response. Fasting baseline serum folate was lower in the obese group (P=0.005); in contrast, red blood cell folate was higher (P=0.05). Area-under-the-curve for the absorption phase (0–3 h) and peak serum folate concentrations were lower in obese versus normal-weight women (P<0.005). Overall serum folate response (0–10 h) was lower in obese versus normal-weight women (repeated-measures ANOVA, P=0.001). Data suggest body distribution of folate is significantly affected by obesity, and, should pregnancy occur, may reduce the amount of folate available to the developing embryo. These findings provide additional support for a BMI-adjusted folic acid intake recommendation for NTD risk reduction.

Altered copper status in adult men with cystic fibrosis.

OBJECTIVES To measure indices of copper status in adult men with cystic fibrosis (CF). A previous study in children showed changes in copper homeostasis compared to controls. This study was designed to investigate whether this observation persisted into adulthood. METHODS This was a case-control age-matched study using seven men with CF and six healthy men. Blood samples were drawn into metal free tubes and fractionated into plasma, polymorphonuclear cells, mononuclear cells and erythrocytes. Cell fractions were assayed for copper and CuZn-superoxide dismutase; plasma was assayed for ceruloplasmin. RESULTS The men with cystic fibrosis had significantly greater plasma copper and ceruloplasmin activity, yet had significantly lower copper-zinc superoxide dismutase activity in mononuclear and polymorphonuclear cells. Furthermore, the mononuclear cells of the cystic fibrosis subjects had about 45% percent less copper-zinc superoxide dismutase protein. Cellular copper levels were not statistically different between the two groups. A significant correlation was found between lung function and copper-zinc superoxide dismutase activity in the polymorphonuclear cells. Iron status was normal. CONCLUSIONS The results indicate that individuals with cystic fibrosis have altered copper distribution compared to control individuals. Some aspects are characteristic of an inflammatory response; however, other measures suggest that copper homeostasis may be abnormal. It is not known whether the deviation in copper homeostasis in these individuals is a result of poor copper absorption, inadequate dietary intake, a result of their chronic inflammation or a direct effect due to the defect in ion transport caused by the disease. However, this research suggests that the severity of the disease and the activity of a copper dependent enzyme may be related. Further work will be necessary to determine the cause of the abnormal copper homeostasis and whether correcting it has any bearing on the course of the disease.

Emerging concepts in nutrigenomics: a preview of what is to come.

This article provides an overview of the fundamental principles of genetics and emerging concepts related to the ways in which nutrients and bioactive food components may interact with the genome and subsequently affect human health. This exciting area of research is likely to have far-reaching implications for the assessment and treatment of critically and chronically ill individuals that will affect nutrition standards of care and practice. A brief overview of some of the ethical, legal, and social implications of genomic research and genome-based health care and a list of genetics resources also are provided.

Folate Deficiency Is Prevalent in Women of Childbearing Age in Belize and Is Negatively Affected by Coexisting Vitamin B-12 Deficiency: Belize National Micronutrient Survey 2011

Background: Folate deficiency, vitamin B-12 deficiency, and anemia can have adverse effects on birth outcomes. Also, low vitamin B-12 reduces the formation of metabolically active folate.Objectives: We sought to establish the baseline prevalence of and factors associated with folate deficiency and insufficiency, vitamin B-12 deficiency, and anemia among women of childbearing age (WCBA) in Belize.Methods: In 2011, a national probability-based survey was completed among Belizean nonpregnant WCBA aged 15-49 y. Blood samples for determination of hemoglobin, folate (RBC and serum), and vitamin B-12 (plasma) and sociodemographic and health information were collected from 937 women. RBC and serum folate concentrations were measured by microbiologic assay (MBA). Folate status was defined based on both the WHO-recommended radioproteinbinding assay and the assay adjusted for the MBA.Results: The national prevalence estimates for folate deficiency in WCBA, based on serum and RBC folate concentrations by using the assay-matched cutoffs, were 11.0% (95% CI: 8.6%, 14.0%) and 35.1% (95% CI: 31.3%, 39.2%), respectively. By using the assay-matched compared with the WHO-recommended cutoffs, a substantially higher prevalence of folate deficiency was observed based on serum (6.9% absolute difference) and RBC folate (28.9% absolute difference) concentrations. The prevalence for RBC folate insufficiency was 48.9% (95% CI: 44.8%, 53.1%). Prevalence estimates for vitamin B-12 deficiency and marginal deficiency and anemia were 17.2% (95% CI: 14.2%, 20.6%), 33.2% (95% CI: 29.6%, 37.1%), and 22.7% (95% CI: 19.5%, 26.2%), respectively. The adjusted geometric means of the RBC folate concentration increased significantly (P-trend < 0.001) in WCBA who had normal vitamin B-12 status relative to WCBA who were vitamin B-12 deficient.Conclusions: In Belize, the prevalence of folate and vitamin B-12 deficiencies continues to be a public health concern among WCBA. Furthermore, low folate status co-occurred with low vitamin B-12 status, underlining the importance of providing adequate vitamin B-12 and folic acid intake through approaches such as mandatory food fortification.

Contribution of seafood to total vitamin B12 intake and status of young adult men and women.

Previous research suggests 20% of omnivores and 40% of vegetarians do not consume enough vitamin B12. The contribution of seafood to dietary B12 intake stratified by frequency of seafood consumption and B12 status of young adults was assessed. Seafood was the greatest contributor to B12 intake (31%) among nonvegetarians, and intake comparisons based on frequency of seafood consumption revealed that frequent seafood consumers had higher (p < 0.001) B12 intakes. None of the frequent seafood consumers had suboptimal status, which occurred mainly in subjects consuming seafood < 1 time/month and vegetarians. Our findings suggest that modest seafood intake contributes to maintaining normal B12 status.

Distinctions in gene-specific changes in DNA methylation in response to folic acid supplementation between women with normal weight and obesity

BACKGROUND/OBJECTIVES Obesity and maternal folate deficiency are associated with increased risk for neural tube defects (NTDs). Limited knowledge exists on the impact of folate status or obesity on DNA methylation of genes related to NTD risk and folate metabolism. SUBJECTS/METHODS Women (18-35y) with normal weight (NW; BMI 18.5-24.9kg/m2; n=12) and obesity (OB; BMI >30kg/m2; n=6) were provided FA (800μg/d) for 8-weeks. Serum folate concentration and changes in DNA methylation across 2098 CpG sites in 91 genes related to NTD risk and folate metabolism were examined. RESULTS Serum folate concentration increased in both groups following FA supplementation, but OB maintained a relative lower concentration (NW; 38.36±2.50-71.41±3.02nmol/L and OB; 27.12±3.09-56.85±3.90nmol/L). Methylation of 56 and 99 CpG sites changed in response to supplementation in NW and OB, respectively, and majority of these sites decreased in methylation in both groups. Only 4 CpG sites responded to supplementation in both groups. Gene ontology analysis revealed a response to supplementation in 61 biological processes (BPs) from the selected genes. Five of the 61 BPs were identified only in NW, including neural tube closure, while 13 of the 61 BPs were enriched only in OB, including folate metabolism, vitamin B12 metabolism and methylation related processes. CONCLUSIONS Changes in DNA methylation in genes related to NTD risk and folate metabolism in response to FA supplementation were different in NW and OB. Increased NTD risk and abnormal folate metabolism in obesity may be due to a distinctive epigenetic response to folate status in these genes.