Folate - Folic Acid Benefits
Folate and folic acid are two different forms of vitamin B9. While folate is the naturally occurring form, folic acid is the synthetic, industrially produced version. Despite this difference, the term folic acid is often used as a synonym for folate. Unlike folates, folic acid is the more chemically stable form 1. Consequently, folate is lost in significant amounts starting from the time of harvest. This trend continues through the storage and processing of food. As a result, about half to three-quarters of the initial folate activity can be lost during these processes 2. Folate is classified as a micronutrient and vitamin.
The word "folate" is derived from the Latin word "folium," which means leaf. Leafy vegetables are generally a very good source of folate. However, some foods such as plant-based drinks or multivitamin juices are often fortified with folic acid. Folate belongs to the group of B-vitamins. In very rare cases, folate is referred to as vitamin B11 or vitamin M. Folate is highly soluble in water. 3. In its pure form, folate or folic acid is a yellow or yellowish-orange crystalline powder. 4.
The essential vitamin B9 needs to be obtained daily through diet, as the body cannot produce it on its own and can only store it in small amounts, with excess amounts being lost through urine. 5. It is believed that approximately 50% of the folate stored in the body (6 to 14 mg) is located in the liver. 6 Therefore, the total amount of folate in the body would range from 12 to 28 mg according to scientists.
To learn about foods rich in folic acid and folate (vitamin B9), click here.
Influence of Vitamin B2 and Vitamin B12 on the functionality of folate
In food, folates are bound to a chain of amino acids known as polyglutamates. These polyglutamates are eliminated in the digestive tract and transformed into folate monoglutamates, which are absorbed through the intestinal mucosa 7. Before the monoglutamates enter the bloodstream, they are reduced to tetrahydrofolate (THF) in the liver and converted into methyl and formyl forms, with 5-methyltetrahydrofolate (abbreviated as 5-Methyl-THF) being the most common form in blood plasma 8.
- Vitamin B2 (Riboflavin): In order for 5-methyltetrahydrofolate (5-MTHF) to be formed, THF is converted to 5,10-methylenetetrahydrofolate (5,10-methylene-THF), which is then further converted to 5-methyl-THF. The enzyme responsible for this conversion is methyltetrahydrofolate reductase (MTHFR). The functionality of the MTHFR enzyme requires the coenzyme flavin adenine dinucleotide (FAD), which contains riboflavin (vitamin B2). Foods high in vitamin B2 can be found here (see vitamin B2 food sources table).
- Vitamin B12: In order to remove the methyl group from 5-methyl-THF and convert folate into its active form (tetrahydrofolate, abbreviated as THF) in the body, vitamin B12 (cobalamin) is required as a cofactor (a low molecular weight substance that contributes to the functioning of an enzyme) for the enzyme methionine synthase 9. In this process, a methyl group (-CH3) is removed from 5-methyl-THF and initially transferred to cobalamin, forming methylcobalamin 10. Subsequently, the methyl group is transferred to homocysteine, resulting in the formation of the amino acid methionine 11 12. If there is a deficiency of vitamin B12, the cycle does not function properly. The body is no longer able to convert folate into its active form. A deficiency of Vitamin B12 thus triggers symptoms of folate deficiency as well. To learn about foods high in vitamin B12, click here: Foods high in vitamin B12.
Functions and Benefits
Folate plays a role in one-carbon metabolism. The coenzyme form of folate is tetrahydrofolate (THF), also known as tetrahydrofolic acid. Tetrahydrofolic acid is required for the transfer of one-carbon units that occur in metabolism. The coenzymes act as acceptors and donors 13. The transport mechanism is required in a number of metabolic reactions involving nucleic acids and amino acids:
- Thus, the coenzymes in the form of 10-formyltetrahydrofolate (a form of THF) are needed for the synthesis of purines, and in the form of 5,10-methylene-THF, they are needed for thymidine nucleotide synthesis 14 15. Purines and nucleotides are building blocks of nucleic acids, thus components of DNA. Therefore, folate metabolism is important for DNA synthesis and repair.
- Folate coenzymes are required for the formation of methionine from homocysteine (methionine synthase). 16. The remethylation process (using 5-methyl-THF) lowers elevated homocysteine levels, which are associated with a range of cardiovascular diseases. Additionally, methionine is needed for the formation of S-adenosylmethionine (SAM). SAM is the primary donor of methyl groups (-CH3) in the body. Methyl groups are transferred to DNA, RNA, proteins, and other important molecules. 17. This process is referred to as methylation.
DNA methylation ultimately plays an important role in the control of gene expression 18. This means that the methylation systems ensure proper functioning of cellular processes because these methylation systems are crucial controls for how cells utilize genes 19. Therefore, folate assists in the formation of red blood cells and DNA 20.
In addition, methylation (folate cycle) is also necessary for the synthesis and regeneration of tetrahydrobiopterin 21. Tetrahydrobiopterin is a cofactor for enzymes that convert amino acids into neurotransmitters (serotonin, melatonin, dopamine, norepinephrine, adrenaline) and nitric oxide.
In summary, folate plays an important biological role as a cofactor or coenzyme in the maintenance and repair of the genome, regulation of gene expression, amino acid metabolism, formation of neurotransmitters, and myelin 22. Neurotransmitters (required for signal transmission) and myelin (insulating layer for nerve cells) are essential for the proper functioning of the nervous system.
Folate / Folic Acid during Pregnancy and Conception
Folate plays an incredibly important role in the development of the nervous system during pregnancy 23. Adequate folate intake should be considered when trying to conceive. Folate is needed for rapid cell proliferation, uterine and placental tissue growth, fetal growth, and expansion of maternal blood volume 24.
In addition, folate is necessary to prevent neural tube defects during early fetal development 25. Neural tube defects such as spina bifida and anencephaly are malformations of the early central nervous system during embryonic development. Therefore, the daily requirement is also increased for pregnant and lactating women.
According to a 2012 summary of studies on folic acid supplementation during pregnancy, folic acid has no benefit on birth weight, placental weight, and length of pregnancy. 26.
Natural folates against depression?
Naturally occurring dietary folate has been inversely associated with depression, according to studies. 27. Other variables such as total folate or folic acid intake were not significant. The researchers conclude that the natural form may potentially provide unique protection against depression and brain health.
Using folates and folic acid against cancer?
Numerous studies suggest a connection between folate status in the body and a reduced risk of various types of cancer (including colorectal, lung, pancreatic, esophageal, stomach, cervical, ovarian, breast, and other types) 28.
Naturally occurring folate could potentially reduce the risk of various types of cancer 29 30. According to a 2005 summary of studies, the results support the notion that folate has a slight protective benefit against colorectal cancer 31. However, scientists cannot definitively rule out confusion with other dietary factors. In a large and more recent study from 2011 involving over 525,000 individuals aged 50 to 71, those consuming 900 µg of folate per day had a 30% lower risk of colorectal cancer compared to those consuming less than 200 µg 32.
In addition, moderate amounts of folic acid could reduce the risk of cancer formation, while high doses of folic acid during cancer (especially colorectal cancer) could accelerate progression 33 34. Another study found no reduction in colorectal tumor risk with a daily administration of 1 mg of folic acid 35. Instead, folic acid is associated with a higher risk of 3 or more adenomas (benign tumors). A summary of studies from 2007 does not recommend folic acid supplementation for colorectal cancer 36. There is insufficient evidence to support the claim that folic acid supplements can protect against cancer 37.
The results of a 2007 study from Malmö show that high folate intake is associated with a lower incidence of postmenopausal breast cancer 38. According to a 2016 study, plasma folate is not associated with reduced cancer risk 39. Instead, it was vitamin B2 and vitamin B6 that could reduce the risk in this study.
The bioavailability indicates how much folate can be absorbed from food and utilized for metabolic processes. However, measuring bioavailability for folate is generally challenging 40. The bioavailability of natural folates depends on the removal of the amino acid chain from the polyglutamates by the intestine 41.
Assuming that no more than 50 to 60% of the folate contained in food can be absorbed 42 43. When folate is added to corresponding foods, about 85% of free folate can be absorbed 44. And folic acid as a dietary supplement can be absorbed 100% when the stomach is empty 45 46.
Vitamin C may potentially improve the bioavailability of folate. In a 2008 study, it was shown that administering 5-methyltetrahydrofolic acid and vitamin C resulted in higher plasma folate concentration compared to the administration of 5-methyltetrahydrofolic acid alone. 47. According to a 2013 study, folate metabolism may be highly dependent on dietary vitamin C intake 48. The table provides information on foods rich in vitamin C.
Are there any considerations for vegans?
With a well-planned vegan diet, there are no issues in meeting the folate requirements 49 50. According to a large British study, vegans have the highest folate intake with an average of 412 μg of vitamin B9 compared to individuals following other dietary forms 51. This is also supported by analyses of two studies from Denmark and Finland, where vegans also have higher intake levels 52 53. According to a small Australian study, 18% of meat eaters and approximately 10% of vegans have a folate deficiency 54. This table shows which foods contain high amounts of folate and folic acid.