Folate and vitamin B-12: friendly or enemy nutrients for the elderly

In the UK vitamin B-12, deficiency occurs in approximately 20% of adults aged >65 years. This incidence is significantly higher than that among the general population. The reported incidence invariably depends on the criteria of deficiency used, and in fact estimates rise to 24% and 46% among free-living and institutionalised elderly respectively when methylmalonic acid is used as a marker of vitamin B-12 status. The incidence of, and the criteria for diagnosis of, deficiency have drawn much attention recently in the wake of the implementation of folic acid fortification of flour in the USA. This fortification strategy has proved to be extremely successful in increasing folic acid intakes pre-conceptually and thereby reducing the incidence of neural-tube defects among babies born in the USA since 1998. However, in successfully delivering additional folic acid to pregnant women fortification also increases the consumption of folic acid of everyone who consumes products containing flour, including the elderly. It is argued that consuming additional folic acid (as 'synthetic' pteroylglutamic acid) from fortified foods increases the risk of 'masking' megaloblastic anaemia caused by vitamin B-12 deficiency. Thus, a number of issues arise for discussion. Are clinicians forced to rely on megaloblastic anaemia as the only sign of possible vitamin B-12 deficiency? Is serum vitamin B-12 alone adequate to confirm vitamin B-12 deficiency or should other diagnostic markers be used routinely in clinical practice? Is the level of intake of folic acid among the elderly (post-fortification) likely to be so high as to cure or 'mask' the anaemia associated with vitamin B-12 deficiency?.

Deficiencies of folate and vitamin B-6 exert distinct effects on homocysteine, serine, and methionine kinetics

Folate and vitamin B-6 act in generating methyl groups for homocysteine remethylation, but the kinetic effects of folate or vitamin B-6 deficiency are not known. We used an intravenous primed, constant infusion of stable isotope-labeled serine, methionine, and leucine to investigate one-carbon metabolism in healthy control (n = 5), folate-deficient (n = 4), and vitamin B-6-deficient (n = 5) human subjects. The plasma homocysteine concentration in folate-deficient subjects [15.9 +/-2.1 (SD) mu mol/l] was approximately two times that of control (7.4 +/-1.7 mmol/l) and vitamin B-6-deficient (7.7 +/-2.1 mmol/l) subjects. The rate of methionine synthesis by homocysteine remethylation was depressed (P = 0.027) in folate deficiency but not in vitamin B-6 deficiency. For all subjects, the homocysteine remethylation rate was not significantly associated with plasma homocysteine concentration (r = -0.44, P = 0.12). The fractional synthesis rate of homocysteine from methionine was positively correlated with plasma homocysteine concentration (r = 0.60, P = 0.031), and a model incorporating both homocysteine remethylation and synthesis rates closely predicted plasma homocysteine levels (r = 0.85, P = 0.0015). Rates of homocysteine remethylation and serine synthesis were inversely correlated (r = -0.89, P < 0.001). These studies demonstrate distinctly different metabolic consequences of vitamin B-6 and folate deficiencies.

Response of red blood cell folate to intervention: implications for folate recommendations for the prevention of neural tube defects

Committees worldwide have set almost identical folate recommendations for the prevention of the first occurrence of neural tube defects (NTDs). We evaluate these recommendations by reviewing the results of intervention studies that examined the response of red blood cell folate to altered folate intake. Three options are suggested to achieve the extra 400 mu g folic acid/d being recommended by the official committees: increased intake of folate-rich foods, dietary folic acid supplementation, and folic acid fortification of food. A significant increase in foods naturally rich in folates was shown to be a relatively ineffective means of increasing red blood cell folate status in women compared with equivalent intakes of folic acid-fortified food, presumably because the synthetic form of the vitamin is more stable and more bioavailable. Although folic acid supplements are highly effective in optimizing folate status, supplementation is not an effective strategy for the primary prevention of NTDs because of poor compliance. Thus, food fortification is seen by many as the only option likely to succeed. Mandatory folic acid fortification of grain products was introduced recently in the United States at a level projected to provide an additional mean intake of 100 mu g folic acid/d, but some feel that this policy does not go far enough. A recent clinical trial predicted that the additional intake of folic acid in the United States will reduce NTDs by >20%, whereas 200 mu g/d would be highly protective and is the dose also shown to be optimal in lowering plasma homocysteine, with possible benefits in preventing cardiovascular disease. Thus, an amount lower than the current target of an extra 400 mu g/d may be sufficient to increase red blood cell folate to concentrations associated with the lowest risk of NTDs, but further investigation is warranted to establish the optimal amount.

Fortification with low amounts of folic acid makes a significant difference in folate status in young women: implications for the prevention of neural tube defects

Background: Mandatory fortification of grain products with folic acid was introduced recently in the United States, a policy expected to result in a mean additional intake of 100 mu g/d. One way of predicting the effectiveness of this measure is to determine the effect of removing a similar amount of folic acid as fortified food from the diets of young women who had been electively exposed to chronic fortification.

Objective: The objective was to examine the effect on folate status of foods fortified with low amounts of folic acid.

Design: We investigated the changes in dietary intakes and in red blood cell and serum concentrations of folate in response to removing folic acid-fortified foods for 12 wk from the diets of women who reportedly consumed such foods at least once weekly (consumers).

Results: Consumers (n = 21) had higher total folate intakes (P = 0.002) and red blood cell folate concentrations (P = 0.023) than nonconsumers (women who consumed folic acid-fortified foods less than once weekly; n = 30). Of greater interest, a 12-wk intervention involving the exclusion of these foods resulted in a decrease in folate intake of 78 +/- 56 mu g/d (P < 0.001), which was reflected in a significant reduction in red blood cell folate concentrations (P < 0.05).

Conclusions: Cessation of eating folic acid-fortified foods resulted in removing 78 mu g folic acid/d from the diet. Over 12 wk this resulted in a lowering of red blood cell folate concentrations by 111 nmol/L (49 mu g/L). This magnitude of change in folate status in women can be anticipated as a result of the new US fortification legislation and is predicted to have a significant, although not optimal, effect in preventing neural tube defects.

Effect of increasing dietary folate on red-cell folate: Implications for prevention of neural tube defects

Background Recommendations by the UK Department of Health suggest that protection from neural tube defects (NTD) can be achieved through intakes of an extra 400 mu g daily of folate/folic acid as natural food, foods fortified with folic acid, or supplements. The assumption is that all three routes of intervention would have equal effects on folate status.

Methods We assessed the effectiveness of these suggested routes of intervention in optimising folate status. 62 women were recruited from the University staff and students to take part in a 3-month intervention study. Participants were randomly assigned to one of the following five groups: folic acid supplement (400 mu g/day; I); folic-acid-fortified foods (an additional 400 mu g/day; II); dietary folate (an additional 400 mu g/day; III); dietary advice (IV), and control (V). Responses to intervention were assessed as changes in red-cell folate between preintervention and postintervention values.

Findings 41 women completed the intervention study. Red-cell folate concentrations increased significantly over the 3 months in the groups taking folic acid supplements (group I) or food fortified with folic acid (group II) only (p<0.01 for both groups). By contrast, although aggressive intervention with dietary folate (group III) or dietary advice (group IV) significantly increased intake of food folate (p<0.001 and p<0.05, respectively), there was no significant change in folate status.

Interpretation We have shown that compared with supplements and fortified food, consumption of extra folate as natural food folate is relatively ineffective at increasing folate status. We believe that advice to women to consume folate-rich foods as a means to optimise folate status is misleading.

Depression associates with Mini Nutritional Assessment (MNA), Vitamin B12 and Folate status::Findings from Belfast Elderly Longitudinal Free-Living Ageing STudy (BELFAST)

Introduction: An association between depression and folate has been found in clinical studies. Depression and dementia can contribute to nutritional deficiency. This study clinical depression in in octo/nonagenarians from the BELFAST study.
Method: In the BELFAST study, 38 free-living octo/nonagenarians (mean age 82 years), who apparently well and cognitively intact were followed up at 5 years and assessed using the Geriatric Depression Scale (GDS), Folstein (30 point), Mini Nutritional Assessment Tool (MNA) together with serum folate and vitamin B12 levels.
Results: Mean GDS was 3.4 (SD 2.5), serum folate 7.1 umol/l (SD 5.3) and B12 553 umol/l (458). With mean MNA and Folstein -25.8 (SD 2.7) and 27.6 (SD 2.7) respectively with no sex difference (p = 0.78; p = 0.36). 25% of subjects showed a GDS >5 indicating risk of mild depression and 21% had compromised nutritional status. MNA associated with GDS in male (r2 = 0.56 p = 0.01), but not in female elderly subjects (r2 = 0.01; p = 0.44). GDS score and lower serum folate were associated (r2 = -0.23; p = 0.01).
Conclusion: Overall there was the suggestion that nutritional status and depression might be linked in male subjects at 5 year follow-up in octo/nonagenarians from the BEFLAST study. The lower folate in subjects categorised at risk of mild depression might suggest vitamin supplementation could be useful.

Intakes of dietary folate and other B vitamins are associated with risks of esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis

Folate is implicated in carcinogenesis via effects on DNA synthesis, repair, and methylation. Efficient folate metabolism requires other B vitamins and is adversely affected by smoking and alcohol. Esophageal adenocarcinoma (EAC) may develop through a process involving inflammation [reflux esophagitis (RE)] leading to metaplasia [Barrett’s esophagus (BE)] and carcinoma. Within a population-based, case-control study, we investigated associations between dietary folate and related factors and risks of EAC, BE, and RE. EAC and BE cases had histologically confirmed disease; RE cases had endoscopically visible inflammation. Controls, age-sex frequency matched to EAC cases, were selected through population and general practice registers. Participants underwent structured interviews and completed food-frequency questionnaires. Multivariate ORs and 95% CIs were computed using logistic regression. A total of 256 controls and 223 EAC, 220 BE, and 219 RE cases participated. EAC risk decreased with increasing folate intake (OR highest vs. lowest = 0.56; 95% CI: 0.31, 1.00; P-trend < 0.01). Similar trends were found for BE (P-trend < 0.01) and RE (P-trend = 0.01). Vitamin B-6 intake was significantly inversely related to risks of all 3 lesions. Riboflavin intake was inversely associated with RE. Vitamin B-12 intake was positively associated with EAC. For EAC, there was a borderline significant interaction between folate intake and smoking (P-interaction = 0.053); compared with nonsmokers with high (≥median) folate intake, current smokers with low intakes (<median) had an 8-fold increased risk (OR: 8.15; 95% CI: 3.61, 18.40). The same group had increased BE risk (OR: 2.93; 95% CI: 1.24, 6.92; P-interaction = 0.12). Folate and other dietary methyl-group factors are implicated in the etiology of EAC and its precursors.

Photodegradation of Folate Sensitized by Riboflavin

Folate is shown to react with singlet-excited state of riboflavin in a diffusion controlled reaction and with triplet-excited state of riboflavin in a somewhat slower reaction with (3)k(q) = 4.8 x 10(8) L mol(-1) s(-1) in aqueous phosphate buffer at pH 7.4, ionic strength of 0.2 mol L(-1), and 25 degrees C. Singlet quenching is assigned as photo-induced reductive electron transfer from ground state folate to singlet-excited riboflavin, while triplet quenching is assigned as one-electron transfer rather than hydrogen atom transfer from folate to triplet-excited riboflavin, as the reaction quantum yield, phi = 0.32, is hardly influenced by solvent change from water to deuterium oxide, phi = 0.37. Cyclic voltammetry showed an irreversible two-electron anodic process for folate, E = 1.14 V versus NHE at a scan-rate of 50 mV s(-1), which appears to be kinetically controlled by the heterogeneous electron transfer from the substrates to the electrode. Main products of folate photooxidation sensitized by riboflavin were pterin-6-carboxylic acid and p-aminobenzoyl-L-glutamic acid as shown by liquid chromatographic ion-trap mass spectrometry (LC-IT-MS).