Folate, vitamin B12, vitamin B6 and riboflavin interact by functioning as cofactors within one-carbon metabolism (OCM), a network of interrelated cellular pathways essential for numerous biological processes, including the biosynthesis of DNA, amino acid interconversions and methylation reactions. The pathways of OCM are influenced by endocrine signals and genetic polymorphisms and are particularly responsive to relevant B-vitamin intakes. Physiological changes in healthy pregnancy, leading to a steady decline in B-vitamin status, add another layer of complexity to the regulation of OCM. Although significant advances have been made to improve our understanding of these pregnancy-related changes, no specific reference ranges yet exist for B-vitamin biomarkers in pregnancy to support normal fetal growth without depleting maternal stores. The lack of pregnancy-related criteria for adequacy of B-vitamin status is in turn a major limitation in identifying pregnant women most at risk of B-vitamin deficiency. Another challenge is that the evidence is very limited to provide a basis for establishing pregnancy-specific dietary recommendations for B-vitamins to support successful pregnancy outcomes. In terms of preventing adverse outcomes, periconceptional folic acid supplementation has a proven role, established more than 30 years ago, in protecting against neural tube defect-affected pregnancies and this has been the major focus of public health policy worldwide. This review evaluates the emerging evidence for the less well recognised role of B-vitamins in preventing hypertensive disorders in pregnancy and the intergenerational effects of B-vitamins on offspring neurodevelopment and cognitive performance during childhood. We also consider the underlying biological mechanisms.

Over 30 years ago it was proven beyond doubt that folic acid supplementation of mothers in early pregnancy protects against neural tube defects (NTD) in their babies. Such conclusive scientific evidence led to clear recommendations for women worldwide to take 0⋅4 mg/d folic acid before conceiving and in early pregnancy, but implementing these into effective policy has been problematic. As a result, there has been no change in the incidence of NTD in Ireland, the UK or any other European country over the 25-year period that the current strategy, recommending periconceptional folic acid supplements to women, has been in place. Thus preventable NTD are not being prevented. Notably, in September 2021, the UK government announced that starch is to be fortified with folic acid on a mandatory basis. A similar decision is now urgently needed in Ireland, where rates of NTD are among the highest in the world. A policy of mandatory folic acid fortification of food would be highly effective in preventing NTD because it reaches all women, including those who have not planned their pregnancy. International evidence shows that wherever such a policy has been introduced, it has proved to be effective in reducing rates of NTD in that country. Apart from preventing NTD, the driver of policy in the area, other potential health benefits across the lifecycle can be anticipated from folic acid fortification. Urgent action is needed on implementation of mandatory food fortification with folic acid in Ireland so that mothers and their babies can benefit.

Older adults (≥65 years) are the fastest growing population group. Thus, ensuring nutritional well-being of the ‘over-65s’ to optimise health is critically important. Older adults represent a diverse population – some are fit and healthy, others are frail and many live with chronic conditions. Up to 78% of older Irish adults living independently are overweight or obese. The present paper describes how these issues were accommodated into the development of food-based dietary guidelines for older adults living independently in Ireland. Food-based dietary guidelines previously established for the general adult population served as the basis for developing more specific recommendations appropriate for older adults. Published international reports were used to update nutrient intake goals for older adults, and available Irish data on dietary intakes and nutritional status biomarkers were explored from a population-based study (the National Adult Nutrition Survey; NANS) and two longitudinal cohorts: the Trinity-Ulster and Department of Agriculture (TUDA) and the Irish Longitudinal Study on Ageing (TILDA) studies. Nutrients of public health concern were identified for further examination. While most nutrient intake goals were similar to those for the general adult population, other aspects were identified where nutritional concerns of ageing require more specific food-based dietary guidelines. These include, a more protein-dense diet using high-quality protein foods to preserve muscle mass; weight maintenance in overweight or obese older adults with no health issues and, where weight-loss is required, that lean tissue is preserved; the promotion of fortified foods, particularly as a bioavailable source of B vitamins and the need for vitamin D supplementation.

As individuals seek increasingly individualised nutrition and lifestyle guidance, numerous apps and nutrition programmes have emerged. However, complex individual variations in dietary behaviours, genotypes, gene expression and composition of the microbiome are increasingly recognised. Advances in digital tools and artificial intelligence can help individuals more easily track nutrient intakes and identify nutritional gaps. However, the influence of these nutrients on health outcomes can vary widely among individuals depending upon life stage, genetics and microbial composition. For example, folate may elicit favourable epigenetic effects on brain development during a critical developmental time window of pregnancy. Genes affecting vitamin B12 metabolism may lead to cardiometabolic traits that play an essential role in the context of obesity. Finally, an individual’s gut microbial composition can determine their response to dietary fibre interventions during weight loss. These recent advances in understanding can lead to a more complete and integrated approach to promoting optimal health through personalised nutrition, in clinical practice settings and for individuals in their daily lives. The purpose of this review is to summarise presentations made during the DSM Science and Technology Award Symposium at the 13th European Nutrition Conference, which focused on personalised nutrition and novel technologies for health in the modern world.

Meta-analyses of epidemiological data report that adults who carry a common polymorphism, the MTHFR 677C→T, in the gene encoding the folate-metabolising enzyme methylenetetrahydrofolate reductase (MTHFR) have a 40% increased risk of CVD and an 87% increased risk of hypertension. Riboflavin (vitamin B2), in its co-enzymatic form flavin adenine nucleotide (FAD), is required as a co-factor by MTHFR and previous trials in hypertensive patients have shown a blood pressure lowering response to riboflavin supplementation that is specific to individuals homozygous for this polymorphism (TT genotype). Low folate status is commonly reported in adults with the TT genotype however the effect of this genetic variant on riboflavin status has not previously been investigated. The aim of this study, therefore, was to investigate dietary intake and biomarker status of riboflavin by MTHFR genotype in Irish adults using data from the National Adult Nutrition Survey (2008–2010) (www.iuna.net).

A 4-day semi-weighed food record was used to collect food and beverage intake data from a representative sample of 1500 Irish adults (18–90 years). Dietary intake data were analysed using WISP© based on UK food composition tables (modified to include recipes of composite dishes, nutritional supplements, fortified foods and generic Irish foods that were commonly consumed). Usual intakes were calculated via the NCI-method using SAS© Enterprise Guide. Blood samples (n = 1126) were collected by venepuncture by a trained professional and were processed and analysed using standard operating procedures. Biomarker status of riboflavin was determined by erthyrocyte gluthathione reductase activation coefficient (EGRac), a functional assay that measures the activity of the enzyme glutathione reductase before and after in vitro activation with its prosthetic group FAD; a lower value indicates better status.

It was found that 12% of the population had the TT genotype. As expected, there was no significant difference in riboflavin intake across the genotype (CC, CT or TT) groups. Similarly, no significant genotype differences in riboflavin status (EGRac) were observed (1.36 vs 1.37 vs 1.38 respectively). Overall, 61% of the total population had EGRac values > 1.3, indicative of low/deficient status with no significant difference observed between the genotype groups (60%,61% and 61%, respectively).

These data suggest that riboflavin status is not influenced by the C677T polymorphism in MTHFR in this cohort of nationally representative Irish adults. Further research is needed to see the impact of riboflavin status on blood pressure across the genotype groups in this nationally representative cohort of Irish adults.

Riboflavin (vitamin B2), as the coenzymes flavin mononucleotide (FMN) and flavin dinucleotide (FAD), is essential for oxidation-reduction reactions and energy metabolism. Riboflavin also interacts with vitamin B12, B6 and folate in one-carbon metabolism, and is required for the conversion of dietary vitamin B6 forms to the coenzyme pyridoxal 5’-phosphate (PLP). Biochemical riboflavin status is rarely measured given the lack of convenient and accessible biomarkers. The current gold-standard marker is erythrocyte glutathione reductase activation coefficient (EGRac) that involves laborious sample processing. High prevalence of riboflavin deficiency (EGRac ≥ 1.4) and suboptimal status (EGRac of 1.3–1.39) have been reported in the UK and Ireland; yet the functional significance is unclear. Plasma riboflavin concentration may serve as an alternative indicator; its association with related metabolites has not yet been investigated. Secondary analysis was conducted to determine the change-point of plasma riboflavin with EGRac, to derive a reference interval for plasma riboflavin, and to determine the association of riboflavin status with plasma PLP, using data of 223 older adult women from a cross-sectional study. Fasting blood samples and sociodemographic, anthropometric and dietary data were available for a convenience sample of 223 older adult women. Plasma PLP and related metabolites were quantified using isotope-dilution liquid chromatography-tandem mass spectrometry. The change-point (95% CI) between EGRac and plasma riboflavin occurred at plasma riboflavin concentration of 26.5 (20.5; 32.5) nmol/L (with EGRac of 1.25). The median (IQR) plasma riboflavin concentration was 15.7 (11.2, 23.8); and the upper and lower limits (90%CI) of the central 95% reference interval were 6.70 (6.33, 7.79) and 64.2 (55.0, 74.6) nmol/L, respectively. Plasma PLP (geometric mean (95%CI)) was significantly lower in women with riboflavin deficiency, 54.0 (46.8, 62.2) nmol/L (n = 64), and suboptimal riboflavin status, 56.1 (48.9, 64.3) nmol/L (n = 48), compared to those with riboflavin adequacy, 135 (112, 161) nmol/L (n = 110). Plasma PLP was positively associated with plasma riboflavin concentration after adjustment for total B6 intake, age, ethnicity, BMI, education, household income and C-reactive protein concentration [β (95% CI) = 1.92 (.670, 3.17) nmol/L; p = 0.003]; a significant interaction between plasma riboflavin and total dietary B6 intake was observed (p = 0.024). In conclusion, we are presenting for the first time a reference range for plasma riboflavin concentration and its change-point with EGRac in healthy women. Vitamin B6 status is strongly associated with riboflavin status; more research is needed to elucidate this relationship in a larger sample and ideally intervention study.

Pre-pregnancy obesity is associated with a 2-fold increased risk of Neural Tube Defects (NTD), an effect not explained by lower dietary folate intake, or non-use of folic acid supplements (as recommended globally to women before and in early pregnancy for NTD prevention). While the exact mechanism linking NTD and obesity is poorly understood, it is possible that a compromised status or metabolism of folate and/or of the closely related micronutrients (vitamin B12, B6 and riboflavin) may be involved. To date however, this hypothesis has not been adequately explored. This study therefore aimed to investigate the relationship of obesity with folate and related B vitamin biomarkers in a representative cohort of non-pregnant UK women of reproductive age. Data were accessed from the most recent UK National Diet and Nutrition Survey (NDNS; Years 7–8; 2015–16), a rolling cross-sectional survey designed to gather information from a representative sample of the UK population on nutrient intakes, food consumption and nutritional status. Data for women aged 16–45 years (non B vitamin supplement users; n 364), were extracted on: anthropometry (height, weight, body mass index [BMI] and waist circumference [WC]), dietary intakes of B vitamins and biomarkers for serum and red blood cell folate, vitamin B12 (total serum B12 and holotranscobalamin), vitamin B6 (plasma pyridoxal-5-phosphate [PLP]) and riboflavin (erythrocyte glutathione reductase activation coefficient EGRAac]). Prevalence of overweight and obesity (i.e. BMI: 25–30kg/m2 and > 30kg/m2) was 28% and 22% respectively, whilst abdominal obesity (i.e. WC > 88cm) was present in 31% of the women. Total serum B12 (r -0.215, P 0.012) and PLP (r -0.270, P 0.002) were negatively correlated with WC, with similar, albeit weaker, correlations found for BMI. Correspondingly, women with abdominal obesity compared to those without, had a lower status of total serum B12 (Median values of: 212 v 249 v pmol/L; P 0.049), B6 (31.5 v 40.5 nmol/L; P 0.002) and EGRac (1.43 v 1.36; P 0.031). No differences in B vitamin dietary intake were observed by categories of abdominal obesity. Abdominal obesity may be a risk factor for low status of both vitamins B12 and B6, independently of dietary intake. Further investigation to elucidate the potential underlying mechanism is warranted. These findings also highlight the importance of taking abdominal obesity into account, in addition to BMI, when examining possible adverse impacts of obesity on micronutrient status.

Periconceptional folic acid (FA) has an established role in the prevention of neural tube defects (NTDs), leading to global recommendations for FA supplementation before and in early pregnancy. However, it is unclear whether there are any benefits for offspring brain health arising from continued maternal FA supplementation beyond the first trimester. The aim of this study was to investigate the role of maternal folate nutrition during pregnancy in relation to cognitive performance and brain function in the offspring at 11 years. The children of mothers who had participated in a randomised trial of Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) were investigated, providing a unique opportunity to examine offspring brain health in relation to maternal folate (the FASSTT Offspring trial; n = 68). Cognitive performance was assessed using the Wechsler Intelligence Scale for Children, Fourth UK Edition (WISC-IV). The WISC-IV measures Full Scale IQ and specific domains of cognitive performance: Verbal Comprehension, Perceptual Reasoning, Working Memory and Processing Speed. Brain function was measured using magnetoencephalography (MEG) in a subset of the child participants (n = 33). The results showed no significant difference in Full Scale IQ between the children of mothers who had received folic acid versus placebo during pregnancy (P = 0.993). Processing Speed subtest scores were however significantly higher in the folic acid group compared with placebo (Symbol Search: P = 0.046 and Cancellation: P = 0.011). The application of MEG analysis showed that at rest, there were differences in brain functioning with significantly lower overall power at Broad band [1–48Hz] (P = 0.041) and a trend (not significant) towards lower power in all other frequency bands (Theta, Mu, Beta, Low Gamma and High Gamma) in children from the FA group compared with placebo. Results for the responses to the language task (congruent and incongruent sentences) in children from the FA group showed significantly lower power within the Theta band [4–8Hz] and significantly higher power within high frequency bands i.e. Beta [13–30 Hz] and High Gamma [49–70 Hz]. This suggested more efficient language processing abilities in these children compared to children of mothers in the placebo group. The findings provide scientific evidence that continuing FA supplementation beyond the periconceptional period that is protective against NTDs, may be beneficial for brain health in the offspring. Furthermore, this study demonstrates that MEG is a useful tool for objective assessment of functional brain activity in healthy children in response to nutrition intervention.

The functional effects of folate within C1 metabolism involve interrelationships with vitamin B12, vitamin B6 and riboflavin, and related gene–nutrient interactions. These B vitamins have important roles throughout life, from pregnancy, through childhood, to middle and older age. Achieving optimal nutritional status for preventing folate-related disease is challenging, however, primarily as a result of the poor stability and incomplete bioavailability of folate from natural food sources when compared with the synthetic vitamin form, folic acid. Thus, in European countries, measures to prevent neural tube defects (NTD) have been largely ineffective because of the generally poor compliance of women with folic acid supplementation as recommended before and in early pregnancy. In contrast, countries worldwide with mandatory folic acid fortification policies have experienced marked reductions in NTD. Low vitamin B12 status is associated with increased risk of cognitive dysfunction, CVD and osteoporosis. Achieving optimal B12 status can be problematic for older people, however, primarily owing to food-bound B12 malabsorption which leads to sub-clinical deficiency even with high dietary B12 intakes. Optimising B-vitamin intake may be particularly important for sub-populations with impaired folate metabolism owing to genetic characteristics, most notably the 677C→T variant in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR). This common folate polymorphism is linked with several adverse health outcomes, including stroke, however, recent evidence has identified its novel interaction with riboflavin (the MTHFR cofactor) in relation to blood pressure and risk of developing hypertension. This review addresses why and how the optimal status of folate-related B vitamins should be achieved through the lifecycle.

SFA intakes have decreased in recent years, both in Ireland and across other European countries; however a large proportion of the population are still not meeting the SFA recommendation of <10% of total energy (TE). High SFA intakes have been associated with increased CVD and type-2 diabetes (T2D) risk, due to alterations in cholesterol homoeostasis and adipose tissue inflammation. PUFA, in particular EPA and DHA, have been associated with health benefits, including anti-inflammatory effects. It is well established that dietary fat composition plays an important role in biological processes. A recent review of evidence suggests that replacement of SFA with PUFA has potential to reduce risk of CVD and T2D. The public health and molecular impact of EPA and DHA have been well-characterised, while less is known of effects of α-linolenic acid (ALA). The current dietary guideline for ALA is 0·5% TE; however evidence from supplementation trials suggests that benefit is observed at levels greater than 2 g/d (0·6–1% TE). This review highlights the gap in the evidence base relating to effects of the replacement of SFA with ALA, identifying the need for randomised controlled trials to determine the optimal dose of ALA substitution to define the efficacy of dietary fat modification with ALA.

Periconceptional folic acid (FA) is known to have a protective effect in the prevention of neural tube defects (NTD), leading to global recommendations for FA supplementation before and in early pregnancy. Maternal folate throughout pregnancy may have other roles in offspring health, including neurodevelopment and cognitive performance in childhood. Folate is essential for C1 metabolism, a network of pathways involved in several biological processes including nucleotide synthesis, DNA repair and methylation reactions. The evidence reviewed here shows a conclusive role for offspring health of maternal folate nutrition in early pregnancy and probable benefits in later pregnancy. Folate-mediated epigenetic changes in genes related to brain development and function offer a plausible biological basis to link maternal folate with effects in offspring brain, albeit this research is in its infancy. Mandatory FA fortification of food has proven to be highly effective in decreasing NTD cases in populations where it has been implemented, but this policy is controversial owing to concerns related to potential adverse effects of over-exposure to FA. In the absence of population-wide fortification, and given the generally poor compliance with current FA recommendations, optimising folate status of mothers in very early pregnancy for protection against NTD remains challenging. Thus, current policy in the UK, Ireland and elsewhere in Europe for the prevention of NTD (based on periconceptional FA supplementation only), has proven to be largely ineffective. This review addresses the evidence and the controversies that surround this area, as well as identifying the challenges in translating policy into practice.

Previous reports investigating adiposity and cognitive function in the population allude to a negative association, although the relationship in older adults is unclear. The aim of this study was to investigate the association of adiposity (BMI and waist:hip ratio (WHR)) with cognitive function in community-dwelling older adults (≥60 years). Participants included 5186 adults from the Trinity Ulster Department of Agriculture ageing cohort study. Neuropsychological assessment measures included the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Multi-variable linear regression models were used to assess the association between adiposity and cognitive function adjusting for insulin resistance, inflammation and cerebrovascular disease. The mean ages were 80·3 (sd 6·7), 71·0 (sd 7·3) and 70·2 (sd 6·3) years on the cognitive, bone and hypertensive cohorts, respectively. In the cognitive cohort, BMI was positively associated with immediate and delay memory, visuospatial/constructional ability, language and MMSE, and negatively with FAB (log-transformed), whereas WHR was negatively associated with attention. In the bone cohort, BMI was not associated with any cognitive domain, whereas WHR was negatively associated with visuospatial/constructional ability, attention and MMSE. In the hypertensive cohort, BMI was not associated with any cognitive domain, whereas WHR was negatively associated with immediate and delayed memory, visuospatial/constructional ability, language and MMSE and positively with FAB (log-transformed). In the cognitive and bone cohorts, the association of WHR and attention disappeared by further controlling for C-reactive protein and HbA1C. In this study of older adults, central adiposity was a stronger predictor of poor cognitive performance than BMI. Older adults could benefit from targeted public health strategies aimed at reducing obesity and obeseogenic risk factors to avoid/prevent/slow cognitive dysfunction.

Globally populations are ageing. By 2050, it is estimated that there will be two billion people aged 60 years or over, of which 131 million are projected to be affected by dementia, while depression is predicted to be the second leading cause of disability worldwide by 2020. Preventing or delaying the onset of these disorders should therefore be a public health priority. There is some evidence linking certain dietary patterns, particularly the Mediterranean diet, with a reduced risk of dementia and depression. Specific dietary components have also been investigated in relation to brain health, with emerging evidence supporting protective roles for n-3 PUFA, polyphenols, vitamin D and B-vitamins. At this time, the totality of evidence is strongest in support of a role for folate and the metabolically related B-vitamins (vitamin B12, vitamin B6 and riboflavin) in slowing the progression of cognitive decline and possibly reducing the risk of depression in ageing. Future studies incorporating new technologies, such as MRI and magnetoencephalography, offer much promise in identifying effective nutrition interventions that could reduce the risk of cognitive and mental disorders. This review will explore the ageing brain and the emerging evidence linking diet and specific nutrients with cognitive function and depression in ageing, with the potential to develop strategies that could improve quality of life in our ageing population.

Evidence suggests that processed red meat consumption is a risk factor for CVD and type 2 diabetes (T2D). This analysis investigates the association between dietary patterns, their processed red meat contributions, and association with blood biomarkers of CVD and T2D, in 786 Irish adults (18–90 years) using cross-sectional data from a 2011 national food consumption survey. All meat-containing foods consumed were assigned to four food groups (n 502) on the basis of whether they contained red or white meat and whether they were processed or unprocessed. The remaining foods (n 2050) were assigned to twenty-nine food groups. Two-step and k-means cluster analyses were applied to derive dietary patterns. Nutrient intakes, plasma fatty acids and biomarkers of CVD and T2D were assessed. A total of four dietary patterns were derived. In comparison with the pattern with lower contributions from processed red meat, the dietary pattern with greater processed red meat intakes presented a poorer Alternate Healthy Eating Index (21·2 (sd 7·7)), a greater proportion of smokers (29 %) and lower plasma EPA (1·34 (sd 0·72) %) and DHA (2·21 (sd 0·84) %) levels (P<0·001). There were no differences in classical biomarkers of CVD and T2D, including serum cholesterol and insulin, across dietary patterns. This suggests that the consideration of processed red meat consumption as a risk factor for CVD and T2D may need to be re-assessed.

The bran and particularly the aleurone fraction of wheat are high in betaine and other physiological methyl donors, which may exert beneficial physiological effects. We conducted two randomised, controlled, cross-over postprandial studies to assess and compare plasma betaine and other methyl donor-related responses following the consumption of minimally processed bran and aleurone fractions (study A) and aleurone bread (study B). For both studies, standard pharmacokinetic parameters were derived for betaine, choline, folate, dimethylglycine (DMG), total homocysteine and methionine from plasma samples taken at 0, 0·5, 1, 2 and 3 h. In study A (n 14), plasma betaine concentrations were significantly and substantially elevated from 0·5 to 3 h following the consumption of both bran and aleurone compared with the control; however, aleurone gave significantly higher responses than bran. Small, but significant, increases were also observed in DMG measures; however, no significant responses were observed in other analytes. In study B (n 13), plasma betaine concentrations were significantly and substantially higher following consumption of the aleurone bread compared with the control bread; small, but significant, increases were also observed in DMG and folate measures in response to consumption of the aleurone bread; however, no significant responses were observed in other analytes. Peak plasma betaine concentrations, which were 1·7–1·8 times the baseline levels, were attained earlier following the consumption of minimally processed aleurone compared with the aleurone bread (time taken to reach peak concentration 1·2 v. 2·1 h). These results showed that the consumption of minimally processed wheat bran, and particularly the aleurone fraction, yielded substantial postprandial increases in plasma betaine concentrations. Furthermore, these effects appear to be maintained when aleurone was incorporated into bread.

Choline is an essential nutrient and can also be obtained by de novo synthesis via an oestrogen responsive pathway. Choline can be oxidised to the methyl donor betaine, with short-term supplementation reported to lower plasma total homocysteine (tHcy); however, the effects of longer-term choline supplementation are less clear. We investigated the effect of choline supplementation on plasma concentrations of free choline, betaine and tHcy and B-vitamin status in postmenopausal women, a group more susceptible to low choline status. We also assessed whether supplementation altered plasma lipid profiles. In this randomised, double-blinded, placebo-controlled study, forty-two healthy postmenopausal women received 1 g choline per d (as choline bitartrate), or an identical placebo supplement with their habitual diet. Fasting blood samples were collected at baseline, week 6 and week 12. Administration of choline increased median choline and betaine concentrations in plasma, with significant effects evident after 6 weeks of supplementation (P < 0·001) and remaining significant at 12 weeks (P < 0·001); no effect was observed on folate status or on plasma lipids. Choline supplementation induced a median (25th, 75th percentile) change in plasma tHcy concentration at week 6 of − 0·9 ( − 1·6, 0·2) μmol, a change which, when compared to that observed in the placebo group 0·6 ( − 0·4, 1·9) μmol, approached statistical significance (P = 0·058). Choline supplementation at a dose of 1 g/d significantly increases the circulating concentration of free choline, and can also significantly increase the concentration of the methyl donor, betaine, thereby potentially enhancing the betaine–homocysteine methyltransferase-mediated remethylation of tHcy. This trial was registered at http://www.controlled-trials.com/ISRCTN82708510.

CVD is the most common cause of death in people over 65 years. This review considers the latest evidence for a potential protective effect of C1 donors (folate and the metabolically related B-vitamins) in CVD. Such an effect may or may not be mediated via the role of these nutrients in maintaining plasma homocysteine concentrations within a desirable range. Despite predictions from epidemiological studies that lowering plasma homocysteine would reduce cardiovascular risk, several secondary prevention trials in at-risk patients published since 2004 have failed to demonstrate a benefit of homocysteine-lowering therapy with B-vitamins on CVD events generally. All these trials were performed in CVD patients with advanced disease; thus current evidence suggests that intervention with high-dose folic acid is of no benefit in preventing another event, at least in the case of heart disease. The evidence at this time, however, is stronger for stroke, with meta-analyses of randomised trials showing that folic acid reduces the risk of stroke, particularly in people with no history of stroke. Genetic studies provide convincing evidence to support a causal relationship between sub-optimal B-vitamin status and CVD. People homozygous for the common C677T variant in the gene encoding the folate-metabolising enzyme, methylenetetrahydrofolate reductase (MTHFR), typically have a 14–21% higher risk of CVD. Apart from folate, riboflavin is required as a co-factor for MTHFR. New evidence shows that riboflavin intervention results in marked lowering of blood pressure, specifically in patients with the MTHFR 677TT genotype. This novel gene–nutrient interaction may provide insights as to the mechanism that links C1 metabolism with CVD outcomes.