Folate Nutrition and Older Adults: Challenges and Opportunities

Dietary Intake Pattern Relates to Plasma Folate and Homocysteine Concentrations in the Framingham Heart Study

Observational studies have linked elevated homocysteine to vascular conditions. Folate intake has been associated with lower homocysteine concentration, although randomised controlled trials of folic acid supplementation to decrease the incidence of vascular conditions have been inconclusive. We investigated determinants of maternal homocysteine during pregnancy, particularly in a folic acid-fortified population. Data were from the Ottawa and Kingston Birth Cohort of 8085 participants. We used multivariable regression analyses to identify factors associated with maternal homocysteine, adjusted for gestational age at bloodwork. Continuous factors were modelled using restricted cubic splines. A subgroup analysis examined the modifying effect of MTHFR 677C>T genotype on folate, in determining homocysteine concentration. Participants were recruited in Ottawa and Kingston, Canada, from 2002 to 2009. Women were recruited when presenting for prenatal care in the early second trimester. In 7587 participants, factors significantly associated with higher homocysteine concentration were nulliparous, smoking and chronic hypertension, while factors significantly associated with lower homocysteine concentration were non-Caucasian race, history of a placenta-mediated complication and folic acid supplementation. Maternal age and BMI demonstrated U-shaped associations. Folic acid supplementation of >1 mg/d during pregnancy did not substantially increase folate concentration. In the subgroup analysis, MTHFR 677C>T modified the effect of folate status on homocysteine concentration. We identified determinants of maternal homocysteine relevant to the lowering of homocysteine in the post-folic acid fortification era, characterised by folate-replete populations. A focus on periconceptional folic acid supplementation and improving health status may form an effective approach to lower homocysteine.

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) microg/d. Spearman correlation coefficients between folate intake and serum and erythrocyte concentrations were 0.14 (P < 0.01) and 0.05 (P = 0.06) respectively. Spearman correlations between folate intakes measured at baseline and after 3 years were 0.58 (P < 0.01). 47% of the participants were classified in the same quartiles on the two occasions. Our FFQ showed a weak correlation between folate intake and blood folate concentrations and reproducibility was acceptable. This FFQ is able to rank subjects according to their folate intake.

Is dietary intake of folate too low?

Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank

Folic Acid Fortification, Folate Status and Plasma Homocysteine

Moderate alcohol consumption is associated with improved vascular risk profile and decreased mortality in the middle aged. An elevated homocysteine concentration is an independent risk factor for cardiovascular disease. To examine the relationship between alcohol consumption and homocysteine concentrations in severely obese patients (body mass index (BMI)>35). A careful alcohol history was obtained from 350 (male:female 1:5) consecutive patients as part of preoperative assessment for surgical treatment of obesity. Data were obtained concerning amount, frequency, timing and type of alcohol consumption. Fasting homocysteine, serum folate and vitamin B(12) concentrations were measured. Differences between groups were assessed using Student t-test, and ANOVA. Linear regression was used to assess factors influencing homocysteine concentration. There is a U-shaped relationship between alcohol consumption and homocysteine concentrations, with light to moderate consumption being associated with lower concentrations. Those consuming <100 g/week (n=165) of alcohol had geometric mean (95% CI of mean) serum homocysteine concentrations of 8.5 (8.2-8.9) micromol/l compared with 9.5 (9.1-9.9) micromol/l for non or rare consumers (n=153; P=0.001). The lower concentrations of homocysteine in regular consumers were associated with higher folate concentrations of 9.4 (8.6-10.2) ng/ml when compared with non-consumers 7.5 (7.1-7.8) ng/ml (P=0.001). Red wine consumers (n=42) had lower fasting concentrations of homocysteine 7.8 (7.5-8.1) micromol/l compared with 153 non-consumers 9.4 (9.0-9.8) micromol/l (P<0.001), 82 beer and spirit consumers 9.0 (8.4-9.7) micromol/l (P=0.005) and 73 white wine consumers 8.8 (8.2-9.4 micromol/l (P=0.013). Red wine consumption was an independent predictor for lower homocysteine concentrations. Mild to moderate alcohol consumption, especially red wine consumption, in obese subjects is associated with lower fasting homocysteine concentrations. This may reduce cardiovascular risk and help explain the 'French paradox'.

PurposeShort telomeres and B vitamin deficiencies have been proposed as risk factors for age-related diseases and mortality that interact through oxidative stress and inflammation. However, available data to support this concept are insufficient. We aimed to investigate the predictive role of B vitamins and homocysteine (HCY) for mortality in cardiovascular patients. We explored potential relationships between HCY, B vitamins, relative telomere length (RTL), and indices of inflammation.MethodsVitamin B6, HCY, interleukin-6 (IL-6), high-sensitive-C-reactive protein (hs-CRP), and RTL were measured in participants of the Ludwigshafen Risk and Cardiovascular Health Study. Death events were recorded over a median follow-up of 9.9 years.ResultsAll-cause mortality increased with higher concentrations of HCY and lower vitamin B6. Patients in the 4th quartile of HCY and vitamin B6 had hazard ratios (HR) for all-cause mortality of 2.77 (95% CI 2.28–3.37) and 0.41(95% CI 0.33–0.49), respectively, and for cardiovascular mortality of 2.78 (95% CI 2.29–3.39) and 0.40 (95% CI 0.33–0.49), respectively, compared to those in the 1st quartile. Multiple adjustments for confounders did not change these results. HCY and vitamin B6 correlated with age-corrected RTL (r = − 0.086, p < 0.001; r = 0.04, p = 0.031, respectively), IL-6 (r = 0.148, p < 0.001; r = − 0.249, p < 0.001, respectively), and hs-CRP (r = 0.101, p < 0.001; r = − 0.320, p < 0.001, respectively). Subjects with the longest telomeres had a significantly higher concentration of vitamin B6, but lower concentrations of HCY, IL-6, and hs-CRP. Multiple regression analyses identified HCY as an independent negative predictor of age-corrected RTL.ConclusionsIn conclusion, hyperhomocysteinemia and vitamin B6 deficiency are risk factors for death from any cause. Hyperhomocysteinemia and vitamin B6 deficiency correlate with increased mortality. This correlation might, at least partially, be explained by accelerated telomere shortening induced by oxidative stress and systemic inflammation in these circumstances.

P87 While blood level of total homocysteine (tHcy) is inversely related to folate intake in cross-sectional studies, few prospective studies have examined changes in tHcy, folate intake, and cardiovascular disease (CVD) risk factors. Serum tHcy was measured on 755 18-30 year old participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study using stored samples from 1985-86 (baseline) and 1992-93 (Year 7), collected prior to food fortification with folic acid. Geometric mean tHcy did not differ by race at baseline (p&gt;0.05). However by Year 7, mean tHcy was higher in blacks than whites (14.3, 13.3, 11.9, 10.9 μmol/L in black men, white men, black women, white women, respectively; p=0.001). Arithmetic mean change in tHcy differed from zero among blacks (1.3-1.4 μmol/L; p&lt;0.001) but not among whites ( -0.3-0.2 μmol/L). Mean folate intake (from diet and supplements) at baseline was higher among whites than blacks within each sex (384, 439, 291, 349 μg, respectively; p=0.001). Although mean folate intake increased in all groups by Year 7, intake was higher among black than white men but the reverse was found among women (517, 496, 339, 421 μg; p for interaction=0.002). In multivariate models, change in tHcy was associated inversely with change in total folate intake in all race-sex groups; changes in smoking status among black men, in serum cholesterol level among whites, and in body mass index among white men were also independent predictors. Thus, tHcy increased over 7 years in blacks by 1.3-1.4 μmol/L (about 1 s.d.) on average, despite increases in folate intake. Changes in CVD risk factor status may help explain this contradictory finding.

This study assessed folate intake, folate concentrations in plasma and erythrocytes, plasma total homocysteine (tHcy) concentrations, and urinary excretion of folate metabolites in Korean women of childbearing age. A total of 36 women voluntarily participated in this study. Precise dietary intake for 3 consecutive days was determined by weighing all foods consumed, and folate intake was calculated with a computer-aided dietary analysis system. Folate concentrations in plasma and erythrocytes were determined via microbiological methods and in plasma by HPLC. Urine excreted over the same period of time was collected and assayed for folate catabolites, para-aminobenzoylglutamate (pABG) and para-acetamidobenzoylglutamate (ApABG) by reverse-phase HPLC after affinity chromatography. The mean folate intake was 206.9+/-90.8 microg DFE/d, and the mean concentrations in plasma and erythrocytes were 10.5+/-3.7 and 249.9+/-77.8 ng/mL, respectively. Erythrocyte folate concentration was low in 2.8% of the subjects (<140 ng/mL) and was marginal in 5.5% (140-156 ng/mL). The mean plasma tHcy concentration was 12.7+/-0.2 nmol/mL, and 11% of the subjects evidenced hyperhomocysteinemia (>or=15 nmol/mL). The mean urinary excretion levels of pABG and ApABG were 10.7+/-3.8 and 89.1+/-19.5 nmol/d, respectively. The means of folate reserve and folate turnover rate were 26.2+/-11.6 and 10.5+/-3.9, respectively. We noted positive relationships between folate intake and the folate concentrations in plasma and erythrocytes, as well as the urinary excretions of ApABG and total folate catabolites. In addition, the erythrocytic folate concentrations were positively associated with the urinary excretions of ApABG and total folate catabolites. In conclusion, the folate status of Korean women of childbearing age was marginally deficient with inadequate concentrations of erythrocyte folate and elevated plasma tHcy, largely due to insufficient folate intake. The marginally deficient folate status was confirmed by the low excretion of folate catabolites in urine.

Background: Randomized trials of supplemental folate and observational studies of circulating folate support a positive association with prostate cancer risk. However, epidemiological studies of dietary and synthetic folate intake are conflicting. Given mandatory folic acid fortification of grains in the US beginning in 1998, evaluation of long-term folate intake from natural and synthetic sources in relation to prostate cancer risk is warranted. Methods: We examined the association between folate intake and prostate cancer risk among 47,884 men in the Health Professionals Follow-up Study who were free from diagnosed cancer at baseline in 1986. Total, natural (from food sources), and synthetic (from supplements/fortification) folate intake was assessed every 4 years using a validated food frequency questionnaire, and categorized as the cumulative average and lagged (0-4, 4-8, 8-12, and 12-16 years in the past) intakes. Cox proportional hazards regression was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (CI). Results: We identified 6,186 incident prostate cancer cases from 1986-2012, including 1,078 with lethal disease (distant metastasis or death). Mean total folate intake was 481 µg/day in 1986 and increased to 671 µg/day by 2010. The proportion of men meeting the recommended intake of 400 µg/day increased from 47% in 1986 to 74% after fortification began in 1998. Folate intake was positively correlated with physical activity, multivitamin use, and PSA testing, and inversely correlated with smoking. Total folate intake averaged over time was not significantly associated with total prostate cancer risk: HR≥800 vs. 400-599=1.03 (95% CI: 0.95-1.13, p-trend=0.76). Neither natural nor synthetic folate intake was associated with risk of total prostate cancer. No associations were observed between total, natural, or synthetic folate intake and risk of lethal, advanced stage, or high-grade disease. Conclusions: Our findings do not support strong associations between intakes of total, natural, or synthetic folate and prostate cancer risk. We found no indication that folate intake of ≥800 µg/day (twice the recommended level) increases prostate cancer risk. Citation Format: Nadine M. Hamieh, Julie L. Batista, Sarah C. Markt, Mary K. Downer, Lorelei A. Mucci, Meir J. Stampfer, Edward L. Giovannucci, Kathryn M. Wilson. Long-term folate intake and prostate cancer risk in the health professionals follow-up study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5314. doi:10.1158/1538-7445.AM2017-5314

Development of a Screening Tool to Assess Folate Intake from Food

Socioeconomic factors are associated with folate and vitamin B12 intakes and related biomarkers concentrations in European adolescents: the Healthy Lifestyle in Europe by Nutrition in Adolescence study

Homocysteine, B-vitamin supplementation, and stroke prevention: from observational to interventional trials

BACKGROUND: Poor compliance to current recommendations of folic acid intake has been observed. Insufficient intakes of folate have been linked to neural tube defects in birth, anemia, neuropsychiatric disorders, some cancers and cardiovascular diseases. OBJECTIVE: The present study aimed to examine folate intake and its relationship with body mass index, physical activity level and intake of other nutrients among female Portuguese university students. METHODS: 67 female students with ages between 19 and 25 years old participated in the study. Dietary intake was assessed by prospective three days food records; physical activity level was evaluated based on reported time spent in several activities. RESULTS: Mean body mass index (BMI) was 22.1 ± 0.4 kg/m 2 (normal weight); mean physical activity level was 1.57 ± 0.02 (low active physical activity level). Mean folate intake was 193.3 ± 9.4g/day, below the recommended dietary allowance of 400g/day. A high prevalence of inadequate folate intake was found (49.2%). CONCLUSIONS: Folate intake was not associated with physical activity categories or BMI values. A positive correlation was found between folate intake, vitamin C and vitamin A intakes. No correlation was found between folate intake and macronutrient intake.