Vitamin B9, or folate, is a member of the B-complex vitamin group. Like all B-vitamins, folate plays vital roles in cellular metabolism and energy production.
More specifically, folate aids in DNA and RNA synthesis, which is especially important during periods of rapid growth (e.g., pregnancy and puberty). Folate also helps control homocysteine levels, which, if too high, can lead to a number of chronic conditions including cancer, heart disease, depression, and diabetes.
What is Vitamin B9/Folate?
Vitamin B9, also known as folate, is a water-soluble essential B vitamin .
The name folate comes from the Latin word folium meaning ‘leaf’ since it is found in many leafy plants. The best dietary sources of folate are green leafy vegetables, citrus fruit juices, and legumes [2, 3].
Folates occur in many chemical forms. They are naturally found in food and the body in the form of metabolically active tetrahydrofolate derivatives (e.g., 5-methyltetrahydrofolate) .
In contrast, folic acid, the synthetic form of Vitamin B9, has no physiological activity unless converted into folates. This primarily occurs in the liver, where folic acid is converted to tetrahydrofolate (THF) using the enzyme dihydrofolate reductase (DHFR) .
5-methyltetrahydrofolate (5-MTHF), the main circulating form of folate, has many essential roles in the body including nucleic acid and amino acid biosynthesis, amino acid conversions, DNA/RNA replication, and methylation, as well as functioning as a cofactor in certain biological reactions .
People with MTHFR polymorphisms require more folate than others.
Health Benefits of Folate:
1) Supports Healthy Fetal Development and Pregnancy
Folate plays a critical role in cell growth during the embryonic phase of fetal development .
Low folate levels in pregnant women are linked to fetal abnormalities, such as neural tube defects (i.e., spina bifida and anencephaly) .
Other studies have found that when taken with a multivitamin supplement, folic acid can minimize the risk of congenital heart defects, cleft lips, and other abnormalities during the preconception period [8, 10].
2) May Reduce the Risk of Cancer
As an essential cofactor for the formation of nucleic acids, folate plays an integral role in DNA synthesis, repair, and stability .
Folate coenzymes also regulate DNA methylation, which is essential in controlling gene expression and cell differentiation. Abnormalities in this process have been linked to the development of mutations and cancer .
Low blood levels of folate are associated with certain types of cancer .
A folate-rich diet has been shown to reduce the risk of a wide variety of cancers (i.e., breast, pancreatic, colon, lung, and esophageal cancers) in a number of observational studies [16, 17, 18, 19, 20, 21].
However, an excess of folic acid intake (above the normal dietary range) may actually accelerate tumor growth in cancer patients, indicating that the role of folate in preventing cancer development depends on the specific dosage .
Folate’s effects in suppressing the initiation of the formation of cancer also appear to be dependent on the status of cell transformation at the time of initial folate exposure. In animal colorectal cancer models, folic acid supplementation was found to prevent cancer development in normal tissues but promote tumor growth in pre-existing regions of abnormal tissue growth [1, 22, 23].
Thus, considerations of both the dose and timing of folate supplementation are critical in preventing cancerous tissue growth .
3) May Prevent Heart Disease
Elevated homocysteine concentrations in the blood are linked to an increased risk of hardening of arteries and heart disease .
In another study, men who consumed higher dietary intakes of folate had lower incidences of strokes and heart attacks .
4) Acts as an Antioxidant
In rats exposed to arsenic, folic acid supplementation was able to mitigate DNA and mitochondrial damage by suppressing oxidative biomarkers (i.e., malondialdehyde (MDA), nitric oxide (NO), and hydroxyl radical (OH(-)) and increasing antioxidant enzyme (e.g., SOD and catalase) activity .
5) Enhances Brain Function
Folate is critical for normal brain development and function .
They are also associated with degeneration of the cerebral cortex, the region of the brain that coordinates learning and memory .
This is likely due to increased homocysteine levels (folate is a cofactor in the reaction that helps convert homocysteine to methionine), which are toxic to neurons and linked to neurodegenerative conditions including Alzheimer’s disease, stroke, and epileptic seizures [35, 34].
In animal models of bacterial meningitis (swelling of the lining covering the brain and spinal cord), increasing folate levels were found to preserve memory function and prevent oxidative damage to the frontal cortex .
Short-term folic supplementation also significantly improved IQ scores, short-term memory, and motor skills in older adults with mild cognitive impairment .
6) Aids in Red Blood Cell Production
This condition is reversible with folic acid treatment .
7) Is a Natural Antidepressant
Depressed patients have lower folate levels .
Increasing folate levels in people with eating disorders led to significant improvements in depressive symptoms .
8) May Prevent Hearing and Vision Loss
One study in the elderly found that higher intakes of folate may reduce the risk of age-related hearing loss .
Age-related macular degeneration (AMD) is one of the major leading causes of blindness in older Americans. A study found that a combined intake of folic acid/vitamin B6/vitamin B12 over 7 years decreased the risk of AMD by 35% to 40% in women at high risk for developing heart disease .
9) Is Anti-Aging
Low-dose folic acid was found to increase the lifespan of roundworms (Caenorhabditis elegans) by boosting oxidative stress resistance factors, indicating that it may be useful for delaying the aging process in humans .
10) Promotes Fertility
In guinea pigs, a short-term deficiency of folate was found to dramatically decrease reproductive performance .
Higher folate intakes are associated with lower frequencies of abnormal sperm (which may interfere with conception) in men .
11) Treats Arsenic Poisoning
Chronic arsenic exposure can increase the risk of cancer, heart disease, and stroke.
A study in arsenic-exposed adults found that folic acid supplementation was able to lower blood arsenic levels by facilitating urinary arsenic excretion .
12) May Ameliorate Autism Spectrum Disorders
Administration of folinic acid (another form of folate) in autistic children with low brain folate levels resulted in an improvement in symptoms and decrease in oxidative biomarkers (which are involved in the progression of autism) [65, 66, 67].
13) Promotes a Healthy Immune System
Increased susceptibility to infection is frequently observed in folate-deficient humans and animals .
Clinical folate deficiency commonly manifests as megaloblastic anemia, a condition that results in impaired immune responses (affecting mainly cell-mediated immunity). Rectifying folate deficiencies with supplementation restores immune function in affected patients .
A folate-rich diet was able to reverse age-related changes in T-cell proliferation and cytokine production in rats, suggesting that folic acid supplementation may be used in the elderly for boosting resistance to infection .
14) Attenuates Liver Damage
Excessive alcohol consumption is a known risk factor for liver disease and cancer. Folic acid intake is associated with counteracting the harmful effects of alcohol on the liver, likely by helping maintain methionine and glutathione levels (both are important for liver detoxification) [72, 73, 74, 75, 76].
15) Ameliorates Kidney Disease
A study in patients with chronic kidney disease found that a combination of enalapril (blood pressure medication) and folic acid was more effective in slowing kidney function decline than enalapril alone. The study recommended the use of folic acid for delaying chronic kidney disease progression in folate-deficient subjects .
Folic acid supplementation also increased survival rates in patients with end-stage kidney disease by alleviating cardiovascular deficits and other kidney disease complications .
16) May Promote Bone Strength
In human osteoclast (bone breakdown cells) cultures, folate depletion resulted in activation of bone resorption (bone loss) activity .
Nitric oxide synthase is an enzyme that helps preserve bone density by stimulating bone formation and preventing bone loss. Folate can act as a cofactor for this enzyme (in absence of its actual cofactor, tetrahydrobiopterin) and promote nitric oxide activity in bone cells, thereby maintaining bone density .
Safety, Risks, Dosing, Interactions:
Since folic acid is water-soluble, it is easily removed from the body through urinary excretion making the risk of toxicity relatively low .
High doses of folate (15 mg/day) for 1 month were associated with sleep disturbances, mental confusion, and gastrointestinal effects in healthy individuals .
Alcohol impairs intestinal folate absorption .
Large doses (e.g., 3,900 mg/day) of nonsteroidal anti-inflammatory drugs (aspirin, ibuprofen, and acetaminophen) may inhibit folate binding and metabolism .
Chronic use of anticonvulsant drugs can interfere with folate absorption .
Folic acid reduces the toxic side effects of methotrexate (a chemotherapeutic and immunosuppressant drug) without impacting its efficacy .
The current Recommended Dietary Allowances for folate (developed by the Food and Nutrition Board (FNB) at the Institute of Medicine of the National Academies):
|0- 6 months||65 mcg DFE||65 mcg DFE|
|7–12 months||80 mcg DFE||80 mcg DFE|
|1–3 years||150 mcg DFE||150 mcg DFE|
|4–8 years||200 mcg DFE||200 mcg DFE|
|9–13 years||300 mcg DFE||300 mcg DFE|
|14–18 years||400 mcg DFE||400 mcg DFE||600 mcg DFE||500 mcg DFE|
|19 and above years||400 mcg DFE||400 mcg DFE||600 mcg DFE||500 mcg DFE|
DFE refers to “Dietary Folate Equivalents”, which were established by the FNB to account for differences in folate bioavailability from foods and supplements. Since folate is more easily absorbed from supplements than from food sources, more food sources of folate are required to yield the same effect, which is why 1mcg from food is equivalent to 0.5mcg in supplements .
DFE is defined as follows :
- 1 mcg DFE = 1 mcg folate found in food
- 1 mcg DFE = 0.6 mcg folic acid from fortified foods or supplements taken with a meal
- 1 mcg DFE = 0.5 mcg folic acid from supplements taken on an empty stomach
- Folate coenzymes (in the form of THF derivatives) accept or donate one-carbon units in key metabolic pathways including nucleic acid and amino acid biosynthetic pathways .
- De novo purine biosynthesis requires 10-formyl-THF .
- Both purine and thymidylate biosynthesis reactions are needed to synthesize DNA/RNA .
- 5-methyl-THF is required to remethylate homocysteine to methionine .
- 5-methyl-THF increases nitric oxide synthase activity .
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