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Functional deficiencies of the essential nutrient folate (folic acid) are common, and can impair key life processes including gene-level regulation, cell growth patterns and tissue repair, from before birth through old age. Best Fully Active Folate provides MTHF (5-methyltetrahydrofolate), the folate form most directly required for DNA regulation and other fundamental metabolic processes. Quatrefolic® is the most bioactive MTHF available anywhere.
• Helps correct inherited and lifestyle-related folate deficiencies*
• Supports healthy mood, memory, circulation and well-being*
MTHF is a cornerstone of human metabolism. It is the body’s ultimate resource for methyl groups (–CH3), which are essential cofactors for numerous enzymes that manage a complex web of metabolic pathways. Methyl groups from MTHF are involved in diverse life processes:
• Synthesis of DNA, RNA and other molecular machinery for protein production.4
• Higher-level gene regulation via activation and deactivation (“epigenesis”).5
• Production of the hormone melatonin6 and the brain transmitters serotonin, dopamine, and noradrenaline.3
• Recycling of the potentially toxic metabolite homocysteine, into nontoxic methionine.4
• Wrapping of nerve cells with myelin protein, to optimize their electrical conductivity.7
• Supplying “one-carbon” groups (mostly as methyl) to drive numerous metabolic reactions.4
Some enzymes use methyl available from MTHF to produce certain purines and pyrimidines, which are building blocks for the bio-synthesis of DNA and RNA.8 DNA is the genetic “blueprint” for making functional proteins, while RNA helps translate the blueprint into the final protein structure. MTHF is the body’s ultimate methyl reservoir, its most dependable source for obtaining methyl groups to build DNA and RNA, and from them proteins and phospholipids as needed.
A gene is a length of DNA with various attached proteins that help regulate the DNA. Various enzymes attach or detach methyl groups to and from the gene’s DNA and its associated proteins, as part of a sophisticated regulatory process called epigenetics. As the term implies, epigenetics is higher-level gene control—in part, the use of methyl as a “toggle switch” for turning each gene off or on.5 Adding methyl turns the gene off, removing methyl turns it on.
High levels of certain proteins in the blood serve as indicators of disruptions to both cardiovascular and immune system health. In a study of 3,258 healthy men, levels of vitamin C in the blood have been found to be inversely associated with these protein markers of unbalanced immune activation.10
Every cell has a distinctive epigenetic pattern that is translated into specific protein patterns, which produce its unique functional profile. In humans with MTHF deficiency, available methyl is limited and can contribute to genetic and epigenetic abnormalities.9 DNA strands can break, DNA repair can be impaired, and other changes can occur that affect gene and chromosome structure.10-12 The deleterious genetic effects of mild folate deficiency have been compared to X-ray exposure (equivalent to approximately 10 times above the maximum X-ray limit considered safe).11
In studies of healthy Australian adults, the third of the population with the lowest folate showed significantly more of these folate deficiency effects.11 Folate deficiency can have epigenetic effects that cascade to cause “downstream” effects on cell structure and function.11,13
MTHF plays a crucial role in the brain’s early development and its ongoing plasticity—the all-important capacity to adapt to changing life circumstances. The brain has very high demand for MTHF, and expends energy to import it across the blood-brain barrier using specialized transport proteins.8 The brain also homeostatically regulates the MTHF in its cerebrospinal fluid (CSF). MTHF levels in the CSF are commensurate with brain health and overall health and wellbeing.
The brain’s reliance on MTHF starts from its very beginning. As the fetal brain begins to form (at about 4-5 weeks after conception) it draws MTHF from the mother’s pool.14 But the body actually stores very little MTHF, so the mother can soon become folate deficient. There is a well- established link between maternal folate deficiency and fetal neural tube defects.14 MTHF deficiency also can afflict newborn babies. Since common foods supply limited amounts of folate, the pregnant women is well advised to supplement with fully active folate—MTHF.
In adults, adequate folate status appears linked to healthy brain structure, including appropriate size of the hippocampus and the amygdala, brain zones important for memory and other cognitive functions.3,15 In this manner, adequate folate intake supports healthy maintenance of memory, healthy mood balance, and all the other higher brain functions.15-17
Several population (epidemiologic) studies in the U.S. and other countries have linked low folate levels to difficulties with mood management.3 When those receiving the highest amounts of folate were compared with those receiving the lowest amounts, the highest folate status was associated with the least severe occurrence of mood difficulties.18 MTHF is gaining mainstream attention as a nutritional component of integrative mood enhancement.19,20
Methyl from MTHF is essential for the body’s production of SAMe (S-adenosylmethionine). SAMe is a highly energized and versatile methyl donor, important for DNA and RNA regulation, for cell membrane phospholipid synthesis, for synthesis of the key antioxidant glutathione, and for numerous other methyl modifications of key biological molecules.21 SAMe supports healthy mood management and many other important life functions.22
In response to the wide prevalence of folate deficiency, the U.S. government instituted food fortification with synthetic folic acid in 1998.23 Despite these efforts, maternal MTHF deficiency is still an issue.23,24 The U.S. Centers for Disease Control and Prevention recommends all women of childbearing age supplement with folate, especially since the need arises during the first trimester when the woman may not be aware she is pregnant.24 MTHF has proven superior to folic acid for this application.
In two double blind trials, MTHF (at 400 mcg per day) outperformed equal amounts of folic acid (also at 400 mcg per day) for raising women’s red cell MTHF levels.25,26 Surveys indicate less than half of all pregnancies in the U.S. are planned, making it prudent for any woman who could become pregnant to consume sufficient MTHF daily.
Another nutrient often strongly recommended during pregnancy is omega-3 DHA (DocosaHexaenoic Acid).27 A clinical study with pregnant women found that those who supplemented with MTHF (400 mcg per day) along with DHA (500 mg per day, with 150 mg per day of EPA), from week 22 until delivery, developed higher levels of blood DHA than those who did not get MTHF.27
Unfortunately, as with the natural folates in foods, folic acid has no metabolic or other nutritional value unless converted into MTHF. The enzyme dihydrofolate reductase (DHFR) must do this conversion, though it is not fully adapted for this task since folic acid is hardly found in nature.28
Studies with human DHFR show that its folic acid converting activity is weak and varies greatly between individuals. DHFR likely cannot convert more than 250 mcg per day of synthetic folic acid into MTHF.29 This level of folic acid intake is actually easy to surpass by consuming fortified foods and/or folic acid supplements,28 so that many people are carrying unconverted, metabolically useless synthetic folic acid in their tissues.30
Recent surveys indicate more than one-third of older U.S. adults have unconverted folic acid in their blood.30 This poses several problems. First, folic acid can negatively interfere with the metabolism of natural folates.28 Second, folic acid in the blood can mask megaloblastic anemia, a clinical sign of vitamin B12 deficiency, whereas MTHF does not have this effect.29 Folic acid’s masking of megaloblastic anemia may allow vitamin B12 deficiency to go undetected. Third, folic acid may inhibit natural killer cells, a class of immune cells that help eliminate other cells which have lost growth control.31
Another liability of synthetic folic acid is that it is not an antioxidant. Folic acid is a highly oxidized molecule28 in contrast to MTHF which is a highly reduced molecule and a potent antioxidant.32 This single feature would strongly recommend MTHF over folic acid for human supplementation. Experts have suggested that one important role for MTHF may be to support the ability of skin to cope with “free radical” damage to its DNA by ultraviolet light.33
Folate deficiency is the most prevalent vitamin deficiency worldwide.8 Besides its potentially crippling effects on the brain14-17 and on cell and tissue growth regulation,8-13 folate deficiency is linked to anemias,34 intestinal dysfunction,8 male fertility problems,35 pollen hypersensitivities,36 and bone thinning.37 Folate deficiency is also linked to blood buildup of homocysteine (HCy), which itself is linked to a plethora of other health problems.4
Poor dietary folate intake is a common cause of folate deficiency, but intestinal or kidney dysfunctions,8 smoking,38 excessive alcohol consumption,8 oral contraceptive use,8,39 and various pharmaceuticals8 all deplete blood MTHF. Women who previously used certain oral contraceptives can have lower folate in the first trimester of their pregnancy, especially if they smoke.39
Another contributor to widespread folate deficiencies is the commonly existing C677T variation in the folate enzyme MTHFR (methylenetetrahydrofolate reductase), which recycles methylenetetrahydrofolate to MTHF. This variation can cause the enzyme to lose well over half its capacity to make MTHF.40 The C677T variation exists in almost half of the individuals in some white populations, and is also common in some other ethnic groups, such as U.S. Hispanics and Puerto Ricans.41 Individuals carrying C677T invariably have low blood MTHF levels.
Homocysteine is a highly reactive, free radical-type substance with proven toxic potential.3 It is a normal byproduct of methionine metabolism that can be routinely recycled to methionine using methyl drawn from MTHF. But when methyl is insufficient (as with MTHF deficiency), HCy is not recycled. HCy then accumulates in the blood and other tissues. Therefore, maintenance of healthy HCy levels—through consistent recycling via MTHF—is an important factor supporting cardiovascular health.3
Homocysteine levels also typically rise with age.3 In several studies with aging subjects,42-44 including one that lasted three years,44 high HCy was correlated with low MTHF status and with the health of blood vessels that supply the brain. Supplementation with MTHF can lower elevated HCy, thereby supporting brain circulation and cognitive function. A 2009 double blind trial examining the leg circulation compared MTHF versus folic acid (both taken at 400 mcg per day).29 MTHF improved pulse wave velocity (PWV), a measure of arterial health, better than did folic acid.
MTHF is the body’s ultimate methyl resource. The human-identical, [6S]-form of MTHF in Best Fully Active Folate is more compatible with human biochemistry than other MTHF forms commercially available. It supplies ample amounts of methyl for the body’s wide range of methyl group applications, helps keep homocysteine at safe levels, and avoids the myriad problems associated with consuming synthetic folic acid.
One capsule taken once a day between meals supplies 400 mcg of highly absorbable Quatrefolic® MTHF. Human studies indicate this daily intake will significantly improve MTHF status regardless of genetic variations in DHFR, MTHFR or other folate handling enzymes. Individuals with life challenges that severely deplete their MTHF stores may do better using higher intakes, under a physician’s supervision.
1. Hannisdal R, Ueland PM, Svardal A. Liquid chromatography–tandem mass spectrometry analysis of folate and folate catabolites in human serum. Clin Chem 2009;55:1147-1154.
2. Huang Y, Khartulyari S, Morales ME, others. Quantification of key red blood cell folates from subjects with defined MTHFR C677>T genotypes using stable isotope dilution liquid chromatography/mass spectrometry. Rapid Commun Mass Spectrom 2008;22:2403-2412.
3. Kronenberg G, Colla M, Endres M. Folic acid, neurodegenerative and neuropsychiatric disease. Curr Mol Med 2009;9:315-323.
4. Blom HJ, Smulders Y. Overview of homocysteine metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis 2011;34:75-81.
5. McGowan PO, Meaney M, Szyf M. Diet and the epigenetic (re)programming of phenotypic differences in behavior. Brain Res 2008;1237:12-24.
6. Fournier I, Ploye F, Cottet-Emard J-M, others. Folate deficiency alters melatonin in rats. J Nutr 2002;132:2781-2784.
7. Hyland K, Shoffner J, Heales S. Cerebral folate deficiency. J Inherit Metab Dis 2010;33:563-570.
8. Wani NA, Hamid A, Kaur J. Folate status in various pathophysiological conditions. IUBMB Life 2008;60:834-842.
9. Ames BN. Prevention of mutation, cancer, and other age-associated diseases by optimizing micronutrient intake. J Nucleic Acids 2010;2010:Article ID 725071, 11 pages.
10. Everson RB, Wehr CM, Erexson GL, McGregor JT. Association of marginal folate depletion with increased human chromosomal damage in vivo. J Natl Cancer Inst 1988;80:525-529.
11. Fenech MF. Dietary reference values of individual micronutrients and nutriomes for genome damage prevention. Am J Clin Nutr 2010;91(suppl):1438S-1454S.
12. Murgia E, Ballardin M, Bonassi S, others. Validation of micronuclei frequency in peripheral blood lymphocytes as early cancer risk biomarker. Mutation Res 2008;639:27-34.
13. Levine AJ, Figueiredo JC, Lee W, others. A candidate gene study of folate-associated one carbon metabolism genes and colorectal cancer risk. Cancer Epidemiol Biomark Prevent 2010;19:1812-1821.
14. Taparia S, Gelineau-van Waes J, Rosenquist TH, Finnell RH. Importance of folate-homocysteine homeostasis during early embryonic development. Clin Chem Lab Med 2007;45:1717-1727.
15. Yang LK, Wong KC, Wu MY, others. Correlations between folate, B12, homocysteine levels, and radiological markers of neuropathology in elderly post-stroke patients. J Am Coll Nutr 2007;26:272-278.
16. Quadri P, Fragiacomo C, Pezzati R, others. Homocysteine, folate, and vitamin B12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr 2004;80:114-122.
17. Ramos MI, Allen LH, Mungas DM, others. Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr 2005;82:1346-1352.
18. Wilkinson AM, Anderson DN, Abou-Saleh MT, others. 5-methyltetrahydrofolate level in the serum of depressed subjects and its relationship to the outcome of ECT. J Affect Disord 1994;32:163-168.
19. Papakostas GI, Petersen T, Lebowitz BD, others. The relationship between serum folate, vitamin B12, and homocysteine levels in major depressive disorder and the timing of improvement with fluoxetine. Int J Neuropsychopharmacol 2005;8:523-528.
20. Ginsberg LD, Oubre AY, Daoud YA. L-methylfolate plus SSRI or SNRI from treatment initiation compared to SSRI or SNRI monotherapy in a major depressive episode. Clin Neurosci 2011;8:19-28.
21. Cederbaum AI. Hepatoprotective effects of S-adenosyl-l-methionine. World J Gastroenterol 2010;16:1366-1376.
22. Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev 2008;13:216-226.
23. Food and Drug Administration. Federal Register 1996;61:8781-8797.
24. Centers for Disease Control. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR 1992;41(www.cdc.gov, accessed 062211).
25. Lamers Y, Prinz-Langenohl R, Bramswig S, Pietrzik K. Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. Am J Clin Nutr 2006;84:156-161.
26. Prinz-Langenohl R, Bramswig S, Tobolski O, others, [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type C677T polymorphism of methylenetetrahydrofolate reductase. Br J Pharmacol 2009;158:2014-2021.
27. Krauss-Etschmann S, Shadid R, Campoy C, others. Effects of fish-oil and folate supplementation of pregnant women on maternal and fetal plasma concentrations of docosahexaenoic acid and eicosapentaenoic acid. Am J Clin Nutr 2007;85:1392-1400.
28. Bailey SW, Ayling JE. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folate acid intake. PNAS 2009;106:15424-15429.
29. Khandanpour N, Armon MP, Jennings B, others. Randomized clinical trial of folate supplementation in patients with peripheral arterial disease. Br J Surgery 2009;96:990-998.
30. Bailey SW, Mills JL, Yetley EA, others. Unmetabolized serum folic acid and its relation to folic acid intake from diet and supplements in a nationally representative of adults aged > or =60 y in the United States. Am J Clin Nutr 2010;92:383-389.
31. Troen AM, Mitchell B, Sorensen B, others. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr 2006;136:189-194.
32. Antoniades C, Shirodaria C, Warrick N, others. Methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels. Circulation 2006;114:1193-1201.
33. Offer T, Ames BN, Bailey DW, others. 5-Methyltetrahydrofolate inhibits photosensitization reactions and strand breaks in DNA. FASEB J 2007;21:2101-2107.
34. Morris MS, Jacques PF, Rosenberg IH, Selhub J. Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors. Am J Clin Nutr 2010;91:1733-1744.
35. Lee HC, Jeong YM, Lee SK, others. Association study of four polymorphisms in three folate-related enzyme genes with non-obstructive male infertility. Hum Reproduction 2006;21:3162-3170.
36. Matsui EC, Matsui W. Higher serum folate levels are associated with a lower risk of atopy and wheeze. J Allergy Clin Immunol 2009;123:1253-1259.
37. McLean RR, Karasik D, Selhub J, others. Association of a common polymorphism in the MTHFR gene with bone phenotypes depends on plasma folate status. J Bone Miner Res 2004;19:410-418.
38. Brown KS, Kluitjmans LAJ, Young IS, others. The 5,10-methylenetetrahydrofolate reductase C677T polymorphism interacts with smoking to increase homocysteine. Atherosclerosis 2004;174:315-322.
39. Bracken MB, Holford TR, White C, Kelsey JL. Role of oral contraception in congenital malformations of offspring. Int J Epidemiol 1978;7:309-317.
40. Botto LD, Yang Q. MTHFR gene variants and congenital anomalies: a HuGE review. Am J Epidemiol 2000; 2000;151:862-877.
41. Garcia-Fragoso L, Garcia-Garcia I, Leavitt G, others. MTHFR polymorphisms in Puerto Rican children with isolated congenital heart disease and their mothers. Int J Genet Mol Biol 2010;2:43-47.
42. Snowdon DA, Tully CL, Smith CD, others. Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings form the Nun Study. Am J Clin Nutr 2000;71:993-998.
43. Weir DG, Molloy AM. Microvascular disease and dementia in the elderly: are they related to hyperhomocystinemia? Am J Clin Nutr 2000;71:859-860.
44. Clarke R, Smith AD, Jobst KA, others. Folate, vitamin B12, and serum total homocysteine levels in Alzheimer’s disease. Arch Neurol 1998;55:1449-1455.
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