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Dietary reference intakes (DRIs) are quantitative, nutrient intake–based standards used for assessing the diets and specific nutrient intakes of healthy individuals and populations and for informing national nutrition policy and nutrition programs. Because nutrition needs vary by age, sex, and physiological state, DRIs are often specified for healthy subgroups within a population. Diet is known to be the leading modifiable risk factor for chronic disease, and the prevalence of chronic disease is growing in all populations globally and across all subgroups, but especially in older adults. It is known that nutrient needs can change in some chronic disease and other clinical states. Disease states and/or disease treatment can cause whole-body or tissue-specific nutrient depletion or excess, resulting in the need for altered nutrient intakes. In other cases, disease-related biochemical dysfunction can result in a requirement for a nonessential nutrient, rendering it as conditionally essential, or result in toxicity for a food component at levels usually tolerated by healthy people, as seen in inborn errors of metabolism. Here we summarize examples from a growing body of literature of disease-altering nutrient requirements, supporting the need to give more consideration to special nutrient requirements in disease states.

Mammals require essential nutrients from dietary sources to support normal metabolic, physiological and neuronal functions, to prevent diseases of nutritional deficiency as well as to prevent chronic disease. Disease and/or its treatment can modify fundamental biological processes including cellular nutrient accretion, stability and function in cells. These effects can be isolated to a specific diseased organ in the absence of whole-body alterations in nutrient status or biochemistry. Loss of blood-brain barrier function, which occurs in in-born errors of metabolism and in chronic disease, can cause brain-specific folate deficiency and contribute to disease co-morbidity. The role of brain folate deficiency in neuropsychiatric disorders is reviewed, as well as emerging diagnostic and nutritional strategies to identify and address brain folate deficiency in blood-brain barrier dysfunction.

Background: Observational studies have shown that low folate and elevated homocysteine concentrations are risk factors for vascular disease in the general population. Randomized controlled trials in vascular patients have failed to show that folic acid reduces the risk of recurrent vascular disease, whereas such trials are lacking in the general population. Objective: The objective was to determine whether folic acid supplementation reduces the progression of atherosclerosis as measured by common carotid intima-media thickness (CIMT) a validated marker of atherosclerosis and predictor of vascular disease risk. Design: A randomized, double-blind, placebo-controlled study in 819 men and postmenopausal women aged 50-70 y, free-living in the Netherlands, and with a total homocysteine concentration >= 13 mu mol/L at screening was conducted. Participants received either 800 mu g folic acid or placebo daily for 3 y. Rate of change in CIMT and arterial distensibility were the primary and secondary outcomes, respectively. Results: Compared with placebo, serum folate increased by 577% and plasma total homocysteine concentrations decreased by 26% after 3 y of folic acid supplementation. The mean (+/- SE) rate of change in CIMT was 1.9 +/- 0.9 mu m/y in the folic acid arm and 1.3 +/- 0.8 mu m/y in the placebo arm (mean difference: 0.7 mu m/y; 95% CI: -1.8, 3.1 mu m/y; P = 0.59). No difference was observed (P = 0.23) between the rates of change in distensibility in the folic acid arm (-0.53 +/- 0.06 x 10(-3) kPa(-1)) and in the placebo arm (-0.62 +/- 0.06 x 10(-3) kPa(-1)). Conclusion: Despite a considerable increase in folate concentrations and a reduction in total homocysteine concentrations, 3-y folic acid supplementation did not slow down atherosclerotic progression or arterial stiffening. This trial was registered at clinicaltrials.gov as NCT00110604. Am J Clin Nutr 2011;93:941-9.

The recommended dietary allowance (RDA) differs between men and women for some vitamins, but not for folate. The RDA for folate is derived mainly from metabolic studies in women. We assessed if men differ from women in their response of erythrocyte folate to folic acid supplementation. We used data from 2 randomized placebo-controlled trials with folic acid: a 3-y trial in which subjects ingested 800 mug/d of folic acid (294 men and 112 women) and a 12-wk trial in which 187 men and 129 women ingested 0, 50, 100, 200, 400, 600, or 800 microg/d of folic acid in a parallel design (n = 38-42 per treatment group). In the 3-y trial, the erythrocyte folate concentration increased 10% (143 nmol/L, [95%CI 46, 241]) less in men than in women. In the 12-wk trial, regression analysis showed that the response of erythrocyte folate upon folic acid intake for men was 47 nmol/L lower than for women (P for beta(gender) = 0.022); for an intake of 800 microg/d folic acid, this resulted in a 5% lower response in men than in women. Differences in lean body size explained 56% of the difference in response of erythrocyte folate between men and women in the 3-y trial and 70% in the 12-wk trial. Men need more folic acid than women to achieve the same erythrocyte folate concentration, mainly because men have a larger lean body mass. This could be an indication that the RDA for folate should be higher for men than for women, or that the RDA should be expressed per kilogram of lean body mass.

Background: Very-long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) are suggested to be related to cognitive performance in older adults. However, limited data exist on the association between n-3 PUFAs and performance in specific cognitive domains. Objective: We evaluated the association between plasma n-3 PUFA proportions and cognitive performance in 5 cognitive domains and determined whether plasma n-3 PUFA proportions predict cognitive change over 3 y. Design: We used data from the FACIT trial, in which participants received folic acid or placebo capsules for 3 y. Fatty acid proportions in plasma cholesteryl esters at baseline were measured in 807 men and women aged 50-70 y. Cognitive performance for memory, sensorimotor speed, complex speed, information-processing speed, and word fluency was assessed at baseline and after 3 y. The crosssectional analyses were based on all 807 participants; the longitudinal analyses were based only on 404 participants in the placebo group. Results: Higher plasma n-3 PUFA proportions predicted less decline in sensorimotor speed (multiple linear regression coefficient, z score = 0.31; 95% CI: 0.06, 0.57) and complex speed (0.40; 95% CI: 0.10, 0.70) over 3 y. Plasma n-3 PUFA proportions did not predict 3-y changes in memory, information- processing speed, or word fluency. The cross-sectional analyses showed no association between plasma n-3 PUFA proportions and performance in any of the 5 cognitive domains. Conclusions: In this population, plasma n-3 PUFA proportions were associated with less decline in the speed-related cognitive domains over 3 y. These results need to be confirmed in randomized controlled trials.

Summary Background Low folate and raised homocysteine concentrations in blood are associated with poor cognitive performance in the general population. As part of the FACIT trial to assess the effect of folic acid on markers of atherosclerosis in men and women aged 50–70 years with raised plasma total homocysteine and normal serum vitamin B 12 at screening, we report here the findings for the secondary endpoint: the effect of folic acid supplementation on cognitive performance. Methods Our randomised, double blind, placebo controlled study took place between November, 1999, and December, 2004, in the Netherlands. We randomly assigned 818 participants 800 μg daily oral folic acid or placebo for 3 years. The effect on cognitive performance was measured as the difference between the two groups in the 3-year change in performance for memory, sensorimotor speed, complex speed, information processing speed, and word fluency. Analysis was by intention-to-treat. This trial is registered with clinicaltrials.gov with trial number NCT00110604. Findings Serum folate concentrations increased by 576% (95% CI 539 to 614) and plasma total homocysteine concentrations decreased by 26% (24 to 28) in participants taking folic acid compared with those taking placebo. The 3-year change in memory (difference in Z scores 0·132, 95% CI 0·032 to 0·233), information processing speed (0·087, 0·016 to 0·158) and sensorimotor speed (0·064, −0·001 to 0·129) were significantly better in the folic acid group than in the placebo group. Interpretation Folic acid supplementation for 3 years significantly improved domains of cognitive function that tend to decline with age.

Vascular disease and its risk factors have been associated with the age-related hearing loss. We examined the association of elevated plasma homocysteine and its determinants with hearing levels. Pure-tone air conduction thresholds in 728 individuals with sensorineural hearing loss were not associated with homocysteine, erythrocyte folate and Vitamin B6. Low concentrations of serum folate and Vitamin B12 were associated with better hearing. When folate status was below the median, 5,10-methylenetetrahydrofolate reductase (MTHFR) 677TT homozygotes had similar hearing levels to subjects with a C allele. However, when folate status was above the median, MTHFR 677TT homozygotes had on an average 5 dB (p = 0.037) and 2.6 dB (p = 0.021) lower PTA-high and PTA-low hearing thresholds, respectively, than the subjects with a 677C allele. The relationship between serum folate and hearing thresholds appeared to be dependent on MTHFR 677 genotype (CC, r = 0.13, p = 0.034; TT, r = -0.10, p = 0.291). This supports the hypothesis that a greater one-carbon moiety commitment to de novo synthesis of nucleotides and an increase in formyl-folate derivatives relative to methyl-folate derivatives is protective for hearing.

Aim: We examined whether total homocysteine, B vitamins and the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T polymorphism are related to common carotid intima-media thickness, a marker of atherosclerosis, and carotid distension, a marker of arterial stiffness. Methods: We used cross-sectional data from 819 individuals aged 50–70 years. B-mode ultrasound of the distal common carotid arteries was performed to determine maximum carotid intima-media thickness, mean carotid intima-media thickness and distension. Results: Carotid intima-media thickness and distension did not differ across homocysteine, serum folate, vitamin B 6 and vitamin B 12 quartiles or between MTHFR C677T genotype. Erythrocyte folate was independently associated with maximum carotid intima-media thickness (mean difference first versus third quartile, 0.03mm, 95% CI 0.004–0.06mm; first versus fourth quartile, 0.03mm, 95% CI −0.002 to 0.06mm). Further adjustment for homocysteine did not affect this association. Folate deficient subjects had greater maximum carotid intima-media thickness than those with high-normal folate concentrations (serum folate: mean difference 0.05mm, 95% CI 0.01–0.08mm; erythrocyte folate: mean difference 0.04mm, 95% CI −0.03 to 0.11mm). Conclusion: Low folate concentrations, independent of hyperhomocysteinemia, may promote atherogenesis. Our findings confirm the null association of homocysteine with carotid intima-media thickness observed in other population-based studies, suggesting that hyperhomocysteinemia does not perpetuate atherosclerosis or arterial stiffness.

Folate, a B vitamin found almost ubiquitously in foods, is required for de novo nucleotide synthesis and methylation reactions in our body. A shortage of folate can lead to macrocytic anemia, however, extra folic acid, the synthetic form of folate, is considered to be a modern day panacea for a variety of diseases, specifically vascular disease. This review summarizes the evidence from randomized controlled trials and illustrates the weak foundation on which health claims regarding the possible beneficial effect of extra folic acid for vascular disease are based. It is prudent for public health policy makers to await trials--the conventional golden standard by which to test causality--before deciding on folic acid fortification for the general population.

This review examines the relationship between hyperhomocysteinemia, a risk factor for vascular disease, and carotid intima-media thickness (CIMT), a valid marker of generalized atherosclerosis and future vascular disease risk. The relationship between two important determinants of hyperhomocysteinemia in the general population-folate status and the 677C --> T methylenetetrahydrofolate reductase (MTHFR) polymorphism-and CIMT is also covered. Methods: We searched literature databases for articles examining homocysteine and CIMT published before September 2003. Results: We identified 54 studies. Observational studies generally failed to demonstrate a relationship between homocysteine and CIMT in homocystinuric, uremic, hypercholesterolemic or non-insulin-dependent diabetes mellitus patients or in subjects with insulin insensitivity. Weak associations, but usually only in certain sub-populations were found in vascular disease patients and in population-based studies. B vitamins reduce the progression of CIMT in renal transplant recipients and vascular disease patients as demonstrated by two trials. The majority of studies demonstrated increased CIMT in individuals with the MTHFR 677TT genotype. Folate status showed no relation to CIMT. Discussion: In non-patient populations, hyperhomocysteinemia is weakly associated with CIMT. The association of the 677C --> T MTHFR polymorphism with CIMT further supports this finding. Lastly, folate levels may need to reach a critically low status before an association can be found between folate and CIMT. Larger trials in various population types are needed to determine whether folate alone or in combination with Vitamins B-6 and B-12 Will slow down or even reverse atherosclerotic progression. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

The present study examined the associations between genetic variation in folate metabolism on the one hand and cognitive functioning and mood on the other in healthy individuals. Two independent population-based samples were used, including 777 participants, aged 24-82 years, from the Maastricht Aging Study (MAAS): and 818 participants, aged 50-70 years, from the Folic Acid and Carotid Intima-Media Thickness (FACIT) study. Thymidylate synthase (75.) 2R -> 3R and serine hydroxymethyltransferase (SHMT1) 1420C -> J polymorphisms were determined in both populations. In addition, the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C -> T polymorphism was determined in the MAAS population. Cognitive performance was assessed in both populations using a neuropsychological test battery. In the MAAS population only, cognitive performance was retested after 12 years of follow-up (n = 612), and mood was measured at baseline (n = 772) and 12-year follow-up (n = 565) by means of the depression subscale of the Symptom Checklist 90. We found that in both study populations, cognitive performance was not associated with TS 2R -> 3R or SHMT1 1420C -> T polymorphisms at baseline, after correction for age, sex, and level of education. The MTHFR 677C -> T polymorphism was not associated with cognitive performance in the MAAS population. None of the polymorphisms in the MAAS population were related to mood at baseline or over 12 years. In conclusion, our findings do not support the involvement of genetic variation in folate metabolism in cognitive performance or mood in healthy individuals.

Contains fulltext : 96148.pdf (Publisher’s version ) (Open Access) A global loss of cytosine methylation in DNA has been implicated in a wide range of diseases. There is growing evidence that modifications in DNA methylation can be brought about by altering the intake of methyl donors such as folate. We examined whether long-term daily supplementation with 0.8 mg of folic acid would increase global DNA methylation compared with placebo in individuals with elevated plasma homocysteine. We also investigated if these effects were modified by MTHFR C677T genotype. Two hundred sixteen participants out of 818 subjects who had participated in a randomized double-blind placebo-controlled trial were selected, pre-stratified on MTHFR C677T genotype and matched on age and smoking status. They were allocated to receive either folic acid (0.8 mg/d; n = 105) or placebo treatment (n = 111) for three years. Peripheral blood leukocyte DNA methylation and serum and erythrocyte folate were assessed. Global DNA methylation was measured using liquid chromatography-tandem mass spectrometry and expressed as a percentage of 5-methylcytosines versus the total number of cytosine. There was no difference in global DNA methylation between those randomized to folic acid and those in the placebo group (difference = 0.008, 95%CI = -0.05,0.07, P = 0.79). There was also no difference between treatment groups when we stratified for MTHFR C677T genotype (CC, n = 76; CT, n = 70; TT, n = 70), baseline erythrocyte folate status or baseline DNA methylation levels. In moderately hyperhomocysteinemic men and women, long-term folic acid supplementation does not increase global DNA methylation in peripheral blood leukocytes.ClinicalTrials.gov NCT00110604.

Although iron homeostasis is essential for brain functioning, the effects of iron levels on cognitive performance in older individuals have scarcely been investigated. In the present study, serum iron parameters and hemochromatosis (HFE) C282Y genotype were determined in 818 older individuals who participated in a 3-year randomized, placebo-controlled double-blind trial examining the effects of folic acid on carotid intima-media thickness. All participants had slightly elevated homocysteine levels and were vitamin B12 replete. Cognitive functioning was assessed at baseline and after 3 years by means of a neuropsychological test battery. At baseline, increased serum ferritin was associated with decreased sensorimotor speed, complex speed, and information-processing speed and increased serum iron was associated with decreased sensorimotor speed. Cognitive performance over 3 years was not associated with HFE C282Y genotype or iron parameters. In conclusion, serum iron parameters do not show a straightforward relationship with cognitive functioning, although elevated iron levels may decrease cognitive speed in older individuals susceptible to cognitive impairment. © The Author 2010. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.

Objectives: Age-related hearing loss is a common social and health problem in the older adult population. Up until now, very little scientific attention has been given to the potential role of fatty acids in age-related hearing loss. In this study we investigated whether plasma very long-chain n-3 polyunsaturated fatty acids (PUFAs) are associated with age-related hearing loss over three years. Design: Cross-sectional and 3-year longitudinal analyses. Setting: Wageningen, the Netherlands. Participants: 720 men and postmenopausal women (50-70 years of age) without middle ear dysfunction or unilateral hearing loss. Measurements: Fatty acid proportions were measured in plasma cholesteryl esters. Hearing thresholds (in decibels, dB) at baseline and after three years were measured with pure-tone audiometry. Hearing loss was calculated as the increase in mean hearing thresholds in the low (0.5-kHz, 1-kHz, and 2-kHz) and high (4-kHz, 6-kHz, and 8-kHz) frequencies over three years. Results: Subjects in the highest quartile of plasma very long-chain n-3 PUFA had less hearing loss in the low frequencies over three years than subjects in the lowest quartile (p

The prevention of neurodegenerative dementias, such as Alzheimer's disease, is a public health priority. Due to the large numbers of affected patients, even interventions bringing about a relatively small delay in disease onset could have large public health effects. Randomized controlled trials (RCTs) are required to demonstrate the effectiveness of preventive interventions, but such trials raise specific methodological questions because they are new in the field of neurodegenerative diseases, and require large numbers of elderly subjects and lengthy follow-up periods. We performed a literature search to identify primary prevention RCTs for neurodegenerative dementia. The methodology of the trials was summarized and discussed during two expert meetings. Overall, 39 trials were identified that assessed dementia incidence or cognitive decline as a primary or secondary study outcome. Age was the most common selection criteria for target populations. Follow-up periods ranged from one month to nine years and were longest in studies measuring dementia incidence as an outcome. Results of RCTs have so far been generally negative and conflicting with those of observational studies, perhaps due to methodological issues. Future trials must therefore carefully consider the target population, outcomes and duration of follow-up to be used, and should assess the problem of attrition.

The recommended dietary allowance (RDA) differs between men and women for some vitamins, but not for folate. The RDA for folate is derived mainly from metabolic studies in women. We assessed if men differ from women in their response of erythrocyte folate to folic acid supplementation. We used data from 2 randomized placebo-controlled trials with folic acid: a 3-y trial in which subjects ingested 800 mug/d of folic acid (294 men and 112 women) and a 12-wk trial in which 187 men and 129 women ingested 0, 50, 100, 200, 400, 600, or 800 microg/d of folic acid in a parallel design (n = 38-42 per treatment group). In the 3-y trial, the erythrocyte folate concentration increased 10% (143 nmol/L, [95%CI 46, 241]) less in men than in women. In the 12-wk trial, regression analysis showed that the response of erythrocyte folate upon folic acid intake for men was 47 nmol/L lower than for women (P for beta(gender) = 0.022); for an intake of 800 microg/d folic acid, this resulted in a 5% lower response in men than in women. Differences in lean body size explained 56% of the difference in response of erythrocyte folate between men and women in the 3-y trial and 70% in the 12-wk trial. Men need more folic acid than women to achieve the same erythrocyte folate concentration, mainly because men have a larger lean body mass. This could be an indication that the RDA for folate should be higher for men than for women, or that the RDA should be expressed per kilogram of lean body mass.

Iron could promote free radical formation, which may lead to injury of the arterial wall and atherosclerosis. Blood donation may reduce cardiovascular risk by lowering body iron status. We collected data on blood donation history and intima-media thickness of the common carotid artery (CIMT) in 819 subjects (50-70 years), who were recruited from municipal and blood bank registries in The Netherlands. Serum iron parameters were assessed, including non-transferrin bound iron (NTBI) that has recently been found in conditions of iron overload. Serum ferritin was lower in current donors (n=443; 44 microg/L) than in ex-donors (n=120; 114 microg/L) and never-donors (n=256; 124 microg/L, P for trend0.001). For NTBI, values were 2.33, 2.54, and 2.51 micromol/L, respectively (P0.05). CIMT was slightly reduced in frequent donors (i.e.,or =49 times during life oror =2 times per year), although not statistically significant. CIMT was not significantly related to NTBI. Frequent blood donation, resulting in lowered body iron, might give some protection against accelerated atherosclerosis.

Folate is required for 1-carbon metabolism and deficiency in folate leads to megaloblastic anemia. Low levels of folate have been associated with increased risk of vascular disease. To investigate whether RDA of folate are met, habitual folate intake needs to be assessed reliably. We developed a FFQ to specifically measure folate intake over the previous 3 months in elderly people in the Netherlands. Major sources of folate intake, i.e. foods contributing to at least 80 % of the average folate intake, were identified through an analysis of the second Dutch Food Consumption Survey for the sub-population of men and women aged 50–70. In 2000 and 2001, folate intake was estimated with this questionnaire in 1286 individuals aged 50–75 years. Concentrations of serum and erythrocyte folate served as biomarkers with which relative validity of the questionnaire was assessed. The same FFQ was repeated after 3 years in 803 subjects in order to assess long-term reproducibility. Mean folate intake was estimated to be 196 (sd 69) μg/d. Spearman correlation coefficients between folate intake and serum and erythrocyte concentrations were 0·14 (P P = 0·06) respectively. Spearman correlations between folate intakes measured at baseline and after 3 years were 0·58 (P

Low folate status has been associated with cognitive decline. We investigated the association of folate Status and the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C --> T polymorphism with performance on a battery of neuropsychological tests. Furthermore, we investigated whether the association of folate with cognitive performance was mediated by plasma homocysteine or risk of vascular disease. We used cross-sectional data from 818 individuals aged 50-70 years old. Low concentrations of erythrocyte folate but not serum folate were associated with poor performance on complex speed and memory tasks, independent of educational level and conventional risk factors of vascular disease. These associations were not mediated by homocysteine concentrations or carotid intima-media thickness. Subjects with the MTHFR 677TT genotype tended to perform better on cognitive tasks than CC/CT subjects, although this was significant for sensorimotor speed only (differences in 7 scores between MTHFR 677TT homozygotes and CC homozygotes -0.15, 95% Cl: -0.30 to 0.00). Low concentrations of erythrocyte folate are associated with decreased cognitive performance, possibly through a homocysteine-independent mechanism Such as DNA infidelity and mitochondrial decay.

SummaryElevated homocysteine levels are associated with an increased cardiovascular disease (CVD) risk, but the underlying mechanism is still unclear. High homocysteine might affect the endothelium, and consequently lead to impaired haemostasis. In a randomized placebo controlled trial among 276 older adults with plasma total homocysteine concentrations above 13 mM at screening, we investigated the effect of homocysteine lowering by folic acid supplementation (0.8 mg/day) for 1 year on markers of endothelial function (vonWillebrand factor), coagulation (tissue factor, factor VIIa, fragments 1+2), and fibrinolysis (fibrin degradation products, tissue-type plasminogen activator), and inflammation (C-reactive protein). Despite a 24% reduction in plasma homocysteine concentration and four-fold increase in serum folate concentration in the folic acid group compared to the placebo group, there was no clear change in any of the haemostasis markers, nor CRP. Although homocysteine is associated with vascular disease risk in the general population, marked lowering of slightly elevated homocysteine concentrations by one-year folic acid supplementation does not influence haemostasis markers.

Contains fulltext : 47488tits.pdf (Publisher’s version ) (Closed access) BACKGROUND: Elevated concentrations of homocysteine and low concentrations of folate may lead to a proinflammatory state that could explain their relation to vascular disease risk. We investigated the effect of lowering homocysteine concentrations by means of folic acid supplementation on markers of inflammation. METHODS: In a double-blind, randomized, placebo-controlled trial among 530 men and postmenopausal women with homocysteine concentrations of 1.8 mg/L or higher (>/=13 micromol/L) at screening, we investigated the effect of folic acid supplementation (0.8 mg/d) vs placebo for 1 year on serum concentrations of C-reactive protein, soluble intercellular adhesion molecule-1, oxidized low-density lipoprotein, and autoantibodies against oxidized low-density lipoprotein. RESULTS: After 1 year of supplementation, concentrations of serum folate increased by 400% (95% confidence interval [CI], 362%-436%), and those of homocysteine decreased by 28% (95% CI, 24%-36%) in the folic acid group compared with the placebo group. However, no changes in plasma concentrations of the inflammatory markers were observed. CONCLUSIONS: Although homocysteine is associated with vascular disease risk in the general population, marked lowering of slightly elevated homocysteine concentrations by means of 1-year folic acid supplementation does not influence inflammatory responses involving C-reactive protein, soluble intercellular adhesion molecule-1, oxidized low-density lipoprotein, and autoantibodies against oxidized low-density lipoprotein.

In their comment on our article, Baggott and Tamura suggest that plasma total homocysteine concentrations may serve as a marker for excess body iron stores. They refer to a study conducted in five healthy volunteers in which non– protein-bound iron was found to catalyze the conversion of thioethers, such as methionine and S-adenosylmethionine, into homocysteine (1). The authors hypothesize that the association between iron stores and homocysteine concentrations may underlie the apparent lack of any significant effects of B-vitamin supplementation on occlusive vascular disease. In our recently published article, we reported that increased concentrations of serum iron and ferritin were associated, cross-sectionally, with decreased cognitive performance in the folic acid and carotid intima-media thickness (FACIT) population (2). Plasma total homocysteine did not confound the observed associations as results were similar regardless if homocysteine concentrations were included in the analyses. We evaluated the relationship between serum iron parameters, HFE C282Y genotype, and plasma total homocysteine in our study sample. We found that carriers of the HFE C282Y mutation did not differ significantly from non carriers in terms of homocysteine concentrations (t = −.677, p = .499). In addition, the concentrations of serum iron, total iron-binding capacity, transferrin saturation, and non– transferrin-bound iron were not significantly correlated with homocysteine concentrations at baseline (r = −.064, p = .068; r = .005, p = .885; r = −.066, p = .060; and r = –.042, p = .236, respectively). However, serum ferritin, which is an indicator of body iron stores, showed a significant positive correlation with plasma total homocysteine at baseline (Spearman’s rank correlation coefficient = .125, p < .001).

Background: Age-related hearing loss is a common chronic condition of elderly persons. Low folate status has been associated with poor hearing. Objective: To determine whether folic acid supplementation slows age-related hearing loss. Design: Double-blind, randomized, placebo-controlled trial conducted from September 2000 to December 2004. Setting: The Netherlands. Participants: 728 older men and women recruited from municipal and blood bank registries with plasma total homocysteine concentrations 13 mu mol/L or greater serum and vitamin B-12 concentrations 200 pmol/L or greater at screening, and no middle ear dysfunction, unilateral hearing loss, or pathologic ear conditions unrelated to aging. Intervention: Daily oral folic acid (800 mu g) or placebo supplementation for 3 years. Measurements: 3-year change in hearing thresholds, assessed as the average of the pure-tone air conduction thresholds of both ears of the low (0.5-kHz, 1-kHz, and 2-kHz) and high (4-kHz, 6-kHz, and 8-kHz) frequencies. Results: Initial median hearing thresholds were 11.7 dB (interquartile range, 7.5 to 17.5 dB) for low frequencies and 34.2 dB (interquartile range, 22.5 to 50.0 dB) for high frequencies. Sixteen participants (2%) were lost to follow-up. After 3 years, thresholds of the low frequencies increased by 1.0 dB (95% CI, 0.6 to 1.4 dB) in the folic acid group and by 1.7 dB (CI, 1.3 to 2.1 dB) in the placebo group (difference, -0.7 dB [CI, -1.2 to -0.1 dB]; P = 0.020). Folic acid supplementation did not affect the decline in hearing high frequencies. Limitations: The strict criterion for participation on the basis of serum homocysteine concentrations limits extrapolation to the general population. Folic acid fortification of food was prohibited in the Netherlands during the study, so baseline folate levels in participants were about half of those found in the U. S. population. Conclusions: Folic acid supplementation slowed the decline in hearing of the speech frequencies associated with aging in a population from a country without folic acid fortification of food. The effect requires confirmation, especially in populations from countries with folic acid fortification programs.