It has been known for decades that babies born to women that have a dietary deficiency in Folic acid (folate) are at increased risk for birth defects, and that the nervous system is particularly susceptible to such defects. Folate deficiency in adults can increase risk of coronary artery disease, stroke, several types of cancer, and possibly Alzheimer's and Parkinson's diseases. Recent findings have begun to reveal the cellular and molecular mechanisms whereby folate counteracts age-related disease. An increase in homocysteine levels is a major consequence of folate deficiency that may have adverse effects on multiple organ systems during aging. Humans with inherited defects in enzymes involved in homocysteine metabolism, including cystathionine beta-synthase and 5,10-methylenetetrahydrofolate reductase, exhibit features of accelerated aging and a marked propensity for several age-related diseases. Homocysteine enhances accumulation of DNA damage by inducing a methyl donor deficiency state and impairing DNA repair. In mitotic cells such DNA damage can lead to cancer, while in postmitotic cells such as neurons it promotes cell death. The emerging data strongly suggest that elevated homocysteine levels increase the risk of multiple age-related diseases, and point to dietary supplementation with folate as a primary means of normalizing homocysteine levels and increasing healthspan.

The study of different neurological problems, including stroke, Alzheimer's disease (AD), and depression, has propelled a greater interest in interrelationships among folate, homocysteine, and neurological function. Specifically, low folate status is a suspected risk factor for depression that also results in an increase in circulating levels of the sulfur amino acid homocysteine. Homocysteine has emerged as an independent risk factor for stroke, and recent studies suggest that vascular disease affecting the brain and Alzheimer's disease may result together in senile dementia. The relationship between stroke and AD was at first interpreted as coincidence, given the pathologic distinctions between the two diseases. However, the connection is now hypothesized to reflect some common pathogenic factors involving folate, homocysteine, or both. It remains unclear whether there is a causal relationship between neurological dysfunction in either condition with folate or homocysteine. Nevertheless, since improvement of folate status lowers homocysteine levels, the hypothesis that folate supplementation may lower the risk of several important health consequences of aging, including various forms of neuropsychiatric dysfunction, is worthy of current intensive exploration.

OBJECTIVES: Risk of having fetus affected with neural tube defects can be reduced by maternal periconceptional Folic acid supplementation. The purpose of the present study is to investigate how folate is taken from diets and to measure plasma folate concentrations. SUBJECTS AND METHODS: A total of 222 women comprising 5 groups, i.e., healthy women, mothers of myelodysplastic patients, pregnant women, myelodysplastic patients, nurse students, participated in our study. Food frequency questionnaires kept 3 days were analyzed based on the 5th standard table of food composition in Japan. Plasma folate concentrations were measured by means of chemiluminescent immunoassay method. Changes in plasma folate concentrations and possible adverse effects following the Folic acid supplementation for 16 weeks were also investigated. RESULTS: The dietary intake of folate, plasma folate concentration and energy intake averaged 293 micrograms/day, 8.1 ng/ml and 1,857 Kcal, respectively, among the subjects. Pregnant women took the largest amount of folate from diets and demonstrated the highest plasma folate concentration among the groups. The dietary folate in myelodysplastic patients and nurse students was significantly lower compared to that of healthy women. The Recommended Dietary Allowance of folate was not fulfilled in 22% of non-pregnant adult women and 72% of pregnant women. The dietary folate was mainly taken from the 3rd food group but the 4th group of food was consumed most. Mean folate intake was significantly correlated with circulating concentrations of serum folate (p = 0.012 r = 0.186). The consecutive administration of 400 micrograms supplements for 16 weeks increased a baseline plasma value of 8.7 ng/ml to 32.6 but fell down rapidly to 17.3 24 hours later without any adverse effects. CONCLUSIONS: The dietary folate and serum folate concentrations averaged 293 micrograms/day and 8.1 ng/ml, respectively. The former is the first report based on the 5th standard table of food composition in Japan. Majority of pregnant women took less dietary folate than what recommended by the government. Those who are capable of becoming pregnant are recommended to consume much of the 3rd food group and those who are planning to become pregnant are recommended to take 400 micrograms of Folic acid supplements from 4 weeks before to 12 weeks after conception.

J Am Coll Cardiol. 2003 Jun 18;41(12):2105-13.
Secondary prevention with folic acid: effects on clinical outcomes.
Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ.
Department of Cardiology, Oosterschelde Ziekenhuizen, Goes, The Netherlands.

OBJECTIVES: We sought to conduct a randomized trial with Folic acid 0.5 mg/day in a patient population with stable coronary artery disease (CAD). BACKGROUND: Folic acid has favorable effects on vascular endothelium and lowers plasma homocysteine levels. In addition, homocysteine appears to be an independent risk factor for atherosclerotic disease. However, the value of Folic acid in secondary prevention had seldom been tested. METHODS: In this open-label study, 593 patients were included; 300 were randomized to Folic acid and 293 served as controls. Mean follow-up time was 24 months. At baseline all patients had been on statin therapy for a mean of 3.2 years. RESULTS: In patients treated with Folic acid, plasma homocysteine levels decreased by 18%, from 12.0 +/- 4.8 to 9.4 +/- 3.5 micromol/l, whereas these levels remained unaffected in the control group (p < 0.001 between groups). The primary end point (all-cause mortality and a composite of vascular events) was encountered in 31 (10.3%) patients in the Folic acid group and in 28 (9.6%) patients in the control group (relative risk 1.05; 95% confidence interval: 0.63 to 1.75). In a multifactorial survival model with adjustments for clinical factors, the most predictive laboratory parameters were, in order of significance, levels of creatinine clearance, plasma fibrinogen, and homocysteine. CONCLUSIONS: Within two years, Folic acid does not seem to reduce clinical end points in patients with stable coronary artery disease (CAD) while on statin treatment. Homocysteine might therefore merely be a modifiable marker of disease. Thus, low-dose folic acid supplementation should be treated with reservation, until more trial outcomes become available.

Women with epilepsy (WWE) have a risk of bearing children with congenital malformations that is approximately twice that of the general population. Most antiepileptic drugs (AEDs) have been associated with such risk. Valproate and carbamazepine have been associated specifically with the development of neural tube defects (NTDs), especially spina bifida. Other factors may contribute to the risk, including concomitant diseases such as diabetes mellitus, occupational exposure to teratogens, excessive prepregnancy weight, and various nutrient deficiencies. In the general population, maternal folate deficiency, in particular, has been linked with the development of NTDs, and periconceptional folate supplementation with a reduction of risk. It is unclear whether folate supplementation has a comparable protective effect for WWE. Data concerning the risk for congenital malformations associated with the newer AEDs (gabapentin, felbamate, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide) are still limited. Several pregnancy registries for women taking AEDs have been established. Comprehensive postmarketing surveillance, regionally or nationally, might be the ideal method of monitoring medication safety, but government support for such an undertaking has for the most part been lacking. Despite uncertainty about the efficacy of periconceptional folate supplementation in WWE, these women should receive such supplementation at dosage levels recommended for the general population of women of childbearing age. Seizure control must not be neglected in a pregnant woman with epilepsy since seizures are associated with harm to the fetus as well as the mother. Risk may be minimized by using a single AED at the lowest effective dosage.

BACKGROUND AND PURPOSE: The introduction of cereal grain Folic acid fortification in 1998 has reduced homocyst(e)ine (tHcy) concentrations in the US population. We performed a case-control study to determine the risk of stroke and transient ischemic attack (TIA) associated with tHcy and low vitamin status in a postfortification US sample. METHODS: Consecutive cases with new ischemic stroke/TIA were compared with matched controls. Fasting tHcy, folate, pyridoxal 5'-phosphate (PLP), B12, and MTHFR 677C-->T genotype were measured. RESULTS: Mean PLP was significantly lower in cases than controls (39.97 versus 84.1 nmol/L, P<0.0001). After stroke risk factors were controlled for, a strong independent association was present between stroke/TIA and low PLP (adjusted odds ratio [OR], 4.6; 95% CI, 1.4 to 15.1; P<0.001) but not elevated tHcy (OR, 0.92; 95% CI, 0.4 to 2.1). CONCLUSIONS: Low B6 but not tHcy was strongly associated with cerebrovascular disease in this postfortification, folate-replete sample.

OBJECTIVE: To evaluate the roles of Folic acid and beta-carotene in the chemoprevention of gastric and other gastrointestinal (GI) cancers. METHODS: In a randomized, double-blind, placebo-controlled trial, a total of 216 patients with atrophic gastritis were randomly assigned to one of the four groups: (1) folate (FA, 20 mg per day plus vitamin B(12) 1 mg, intramuscularly, per month for one year, then 20 mg two times a week plus 1 mg per three months for the next year); (2) natural beta-carotene (N-betaC, 30 mg per day for first year, then 30 mg two times a week for the next); (3) synthetic beta-carotene (S-betaC, administered as in N-betaC); and (4) placebo. Follow-ups continued from 1994 to 2001. RESULTS: A total of 7 new cases of gastrointestinal cancers were diagnosed with 3 stomach, 1 colon and 1 esophageal cancers occurring in the placebo group; 1 stomach cancer in both of the N-betaC and S-betaC groups, and no cancer occurring in FA group. In terms of GI cancers, there was a significant reduction in the FA group, compared with the placebo group (P = 0.04). A similar trend was observed in both N-betaC and S-betaC groups (P = 0.07 - 0.08). Taken together, the three intervention groups displayed a highly significant decrease in occurrence (P = 0.004, vs placebo), and a lower risk for GI cancers (OR = 0.12; 95% confidence interval, 0.03 - 0.51). For development of gastric cancer, any one of the three active-treated groups did not reach statistically significant reduction. The FA group showed obvious improvement of the gastric mucosal lesions with more patients displaying lesions reversed or stable atrophy and inflammation (P = 0.04), reversed intestinal metaplasia (P = 0.06) at the end of follow-up, and reversed displasia (P = 0.017) at 12 months. Two cases of false jaundice were found in beta-carotene groups with no influence on administration, and no side-effects were reported in FA group. CONCLUSIONS: This trial revealed the interventional effect of folic acid on the development of GI cancers, a similar effect of beta-carotene was also detected. Also, Folic acid may be of use to treat atrophic gastritis by preventing or reversing the precancerous lesions.

There a few birth defects known to be preventable, but neural tube defects (NTDs) are one group of congenital anomalies that can potentially be prevented. When 400 micrograms of maternal periconceptional Folic acid is taken daily, it can prevent many neural tube-related birth defects and thus reduce morbidity and mortality due to these birth defects. Health care providers should encourage every woman of reproductive age to consume 400 micrograms of synthetic Folic acid daily, not just those who are planning a pregnancy. Supplementation needs to be started prior to conception for optimal effectiveness.

INTRODUCTION: Endothelial dysfunction is an early manifestation of the atheromatous process and is evident without overt clinical signs or symptoms of the disease. Cigarette smoking has been shown to be associated with endothelial dysfunction in otherwise healthy adults. Although cessation of smoking is the ideal objective, it is not always attainable, and therefore any strategy to prevent early endothelial dysfunction is desirable. Folic acid is currently under review as a rational therapeutic agent in hyperhomocysteinemia. However, Folic acid may modify endothelial function independent of its effect on homocysteine. We therefore investigated the effect of Folic acid on endothelial function in young otherwise healthy cigarette smokers. METHODS: Volunteer cigarette smokers (n = 10) and control lifelong nonsmokers were enrolled in the study. Baseline folate, vitamin B12, homocysteine, and cholesterol levels were analyzed. Flow-mediated dilatation, an endothelial-dependent phenomenon, was assessed using ultrasonography. This scan was performed at baseline and following 4 weeks of Folic acid supplementation (5 mg/day). RESULTS: There were no significant differences in the baseline hematological investigations between the groups. Homocysteine levels were within normal limits in both groups and did not change following Folic acid supplementation. Cigarette smokers demonstrated significant endothelial dysfunction compared to controls (P < 0.005). This difference was significantly attenuated by Folic acid supplementation (P < 0.005). CONCLUSION: Folic acid significantly improves endothelial function in otherwise healthy cigarette smokers. This provides a potential therapeutic tool in attenuating the atheromatous process in this group.

Folate is crucial for normal DNA methylation, synthesis and repair, and deficiency of this nutrient is hypothesized to lead to cancer through disruption of these processes. There is some evidence to suggest that relatively high dietary folate intake might be associated with reduced colorectal cancer risk, especially among individuals with low methionine intake. A case-cohort analysis was undertaken within the cohort of 56,837 women who were enrolled in the Canadian National Breast Screening Study and who completed a self-administered dietary questionnaire. During follow-up to the end of 1993, a total of 389 women were diagnosed with colorectal cancer, identified by linkage to the Canadian Cancer Database. For comparative purposes, a subcohort of 5,681 women was randomly selected from the full dietary cohort at baseline. After exclusions for various reasons, the analyses were based on 295 cases and 5,334 non-cases. Folate intake was inversely associated with colorectal cancer risk (IRR = 0.6, 95% CI = 0.4-1.1, p for trend = 0.25). The inverse association was essentially similar among individuals with low and high methionine intake, and was similar for colon and rectal cancers when those endpoints were analyzed separately. Among individuals with low methionine intake, folate intake did not appear to lower the risk of rectal cancer, a finding that may be due, in part, to the low number of cases in the subgroup analysis. Overall, our data lend some support to the hypothesis that high folate intake is associated with a reduced risk of colorectal cancer.

Higher intakes of Folic acid-rich foods such as vegetables, legumes, and whole grains are associated with lower incidence of carcinomas in international comparisons and case-control studies. Deficiency of Folic acid in experimental studies causes DNA damage that resembles the DNA damage seen in cancer cells. The requirement for Folic acid in DNA synthesis and DNA methylation provides a plausible mechanism for a mutagenic effect of a low-folate diet. It is suggested that cancer can be initiated by DNA damage that results from Folic acid deficiency. The relatively low level of Folic acid in North American diets might be the underlying reason for high rates of many cancers in North America.

BACKGROUND: The Food and Drug Administration (FDA) has recommended that cereal-grain products be fortified with Folic acid to prevent congenital neural-tube defects. Since Folic acid supplementation reduces levels of plasma homocyst(e)ine, or plasma total homocysteine, which are frequently elevated in arterial occlusive disease, we hypothesized that Folic acid fortification might reduce plasma homocyst(e)ine levels. METHODS: To test this hypothesis, we assessed the effects of breakfast cereals fortified with three levels of Folic acid, and also containing the recommended dietary allowances of vitamins B6 and B12, in a randomized, double-blind, placebo-controlled, crossover trial in 75 men and women with coronary artery disease. RESULTS: Plasma Folic acid increased and plasma homocyst(e)ine decreased proportionately with the Folic acid content of the breakfast cereal. Cereal providing 127 microg of Folic acid daily, approximating the increased daily intake that may result from the FDA's enrichment policy, increased plasma Folic acid by 31 percent (P=0.045) but decreased plasma homocyst(e)ine by only 3.7 percent (P= 0.24). However, cereals providing 499 and 665 microg of Folic acid daily increased plasma folic acid by 64.8 percent (P<0.001) and 105.7 percent (P=0.001), respectively, and decreased plasma homocyst(e)ine by 11.0 percent (P<0.001) and 14.0 percent (P=0.001), respectively. CONCLUSIONS: Cereal fortified with folic acid has the potential to increase plasma Folic acid levels and reduce plasma homocyst(e)ine levels. Further clinical trials are required to determine whether Folic acid fortification may prevent vascular disease. Until then, our results suggest that Folic acid fortification at levels higher than that recommended by the FDA may be warranted.

Vitamin B12 in plasma, folic acid in plasma and erythrocytes were examined in 11 patients in the polyuric stage of chronic renal failure without dialyzation treatment, in 38 patients included in a long-term dialyzation programme before and after 3 months' oral administration of Folic acid--(2 X 5 mg week)--and in 23 patients after transplantation of the kidneys. In none of the examined groups vitamin B12) and Folic acid deficiency in plasma was detected. A reduced Folic acid level in erythrocytes, but still in the reference range, was found in patients in the long-term dialyzation programme without supplementation. Supplementation with Folic acid increased its concentration in plasma 4.5 times and in red cells 5.5 times. Haemodialysis did not influence the concentration of the examined indicators in plasma and red cells. According to the recorded results it is not necessary to supplement patients in long-term dialyzation programme and after renal transplantation with vitamin B12 and Folic acid, if their dietary protein intake is not restricted.

Hyperhomocysteinemia is an important cardiovascular risk factor. Serum homocysteine levels are specially dependent on folate nutritional status. In addition, the oxidative modification of low-density lipoproteins (LDLs) in the endothelial microenvironment is a damaging factor that can be modified with fat-soluble antioxidant vitamins. The present study was done to assess the effect of a supplementation of Folic acid and antioxidant vitamins on homocysteine levels and in vitro LDL oxidation in patients with coronary artery disease. Twenty-three patients with angiographically proven coronary artery disease were given supplements for 15 d consisting of one capsule twice a day of a multivitamin preparation containing 0.65 mg Folic acid, 150 mg alpha-tocopherol, 150 mg ascorbic acid, 12.5 mg beta-carotene, and 0.4 microgram vitamin B12. Serum lipids, vitamin and homocysteine levels, and in vitro LDL oxidation were measured before and after the supplementation period. During the supplementation period, serum folate levels increased from 5.0 +/- 1.5 to 10.8 +/- 3.8 ng/mL (P < 0.001), vitamin B12 increased from 317.4 +/- 130.4 to 334.5 +/- 123.8 pg/mL (P < 0.05), and alpha-tocopherol increased from 8.2 +/- 5.1 to 13.7 +/- 7.9 mg/L (P < 0.001). Serum homocysteine levels decreased from 8.7 +/- 4.3 to 6.3 +/- 2.2 mumol/L (P < 0.001). In vitro LDL oxidation decreased from 2.6 +/- 1.1 to 1.6 +/- 1.1 nmol malondialdehyde/mg protein (P < 0.001). In comparing patients with healthy controls, basal levels of folate were lower in the patients, whereas vitamin B12, alpha-tocopherol, and homocysteine levels were similar. No changes in serum lipid levels or body weight were observed. In conclusion, a short-term supplementation with Folic acid and antioxidant vitamins can reduce serum homocysteine levels and in vitro LDL oxidation in patients with coronary artery disease.