Arguably, no conventional nutrient has undergone as much of a research renaissance in recent years as folate. Many people are familiar with the name of this B complex vitamin, and it has long been recognized as a key nutrient in human health. Low intakes of folate can have devastating effects, ranging from birth defects to blood diseases and possibly even cancers.
The adult Dietary Reference Intake (DRI) level for folate is 400 micrograms DFE, where “DFE” stands for “Dietary Folate Equivalents.” In the 2009-2010 National Health and Nutrition Examination Survey (NHANES), both male and female adults in the U.S. averaged well over this amount, with approximately 475 mcg DFE for adult women and 625 mcg DFE for adult men.
As mentioned earlier, the past decade of folate research has taught us much more about the nature of this vitamin and its critical role in support of our health. However, we would also point out that, in general, folate has been a complicated vitamin for researchers to understand, and research on folate has produced some confusion when scientific findings need to get translated into practical steps that we can take in the grocery store and in the kitchen. Our goal in these next paragraphs is provide you with a framework for simplifying key aspects of recent research on this B vitamin.
Let’s start off with the name of the vitamin itself. “Folate” is a very general name for a complicated family of nutrients found in both plant and animal foods. (At WHFoods, we use this very general term as our name for this B vitamin, and when we use it, we are not trying to specify any particular form of the vitamin. We just want to refer to this B vitamin in a consistent way.) To give you an idea of many different folate forms in food, consider the following list: methylfolates, dihydrofolates, monoglutamyl folates, and polyglutamyl folates. All of these vitamin forms can be found in varying amounts in whole, natural foods. By contrast, fortified and enriched foods are typically boosted in content with a single form of this vitamin, namely, folic acid. While you can find not only folic acid but many different forms of folate available in the form of dietary supplements, this vitamin gets added to food almost exclusively in the form of folic acid.
This complicated situation involving fortified foods led the National Academy of Sciences (NAS) to establish a new category for measuring dietary folate, called Dietary Folate Equivalents, or DFEs. If you consume 1 microgram of folate from a whole natural food, the NAS considers you to have consumed 1 microgram DFE. However, if you consume 1 microgram of folate from a food that has been fortified with folic acid, the NAS considers you to have consumed 1.6 micrograms DFE. Finally, if you take a folic acid supplement on an empty stomach in which no foods are simultaneously being consumed, the NAS considers you to have consumed 2 micrograms DFE. These differences in DFE calculation are based on studies measuring blood folate levels following intake of folate in various forms. The higher DFEs reflect higher blood levels associated with intake of supplemental folic acid versus natural food folate.
However, in order to more fully understand the health benefits of this vitamin, it would be a mistake to stop our discussion with consideration of supplemental folic acid, food folate, and DFEs. During the time that has passed since the NAS establishment of folate DFEs in 1998, there have been numerous advances in research on this vitamin. In comparison to the original DFE research, which showed about 50-60% bioavailability of food folate versus 85% bioavailability of supplemental folic acid, we now know that “bioavailable” can have many meanings and blood levels of folate are not always the best way to measure bioavailability. For example, we now know that polyglutamated folate found in vegetables and citrus fruits can be absorbed in the 60-98% range. We also know that a methylated form of folate (5-methyl-tetrahydrofolate) is the major form of folate in most plant cells, and that methylfolate appears to be the only form of this vitamin that crosses over the blood brain barrier and into the brain. This research has greatly increased interest in whole foods and the extent to which they naturally contain methylfolates.
Taken as a whole, these more recent research studies suggest that folate DFEs do not tell the whole story of this vitamin with respect to health benefits, and that whole, natural foods providing folate in a variety of forms are likely to be your best bet for obtaining health benefits related to this B vitamin. With this general guideline in mind, we would like to highlight specific areas in which folate health benefits have been most consistently documented in research studies.
Folate has long been known to help support production of nervous system function, and in particular, production of messaging molecules that are used by nerves to send signals throughout out body. More recently, however, research has broadened our understanding in this area of folate benefits.
In what has come to be named the BH4 Cycle (where is an abbreviation for tetrahydrobiopterin), researchers have verified a close connection between production of multiple neurotransmitters (with special emphasis on serotonin and dopamine) and availability of folate. In fact, part of the molecule for which this BH4 Cycle is named (dihydrobiopterin, or BH2) can itself be readily converted into a form of folate (dihydrofolate). In addition, researchers now know that BH4 cross over the blood brain barrier using the same transport mechanism as folate.
Interest in these nervous system messaging molecules and folate has been fascinating and widespread. Since much of the dopamine produced in our nerve cells begins with conversion of one amino acid (phenylalanine) into another amino acid (tyrosine), folate availability has been shown to be closely connected with this neurotransmitter pathway since BH4 is required for conversion of phenylalanine into tyrosine. Yet broader still are possible connections between two additional neurotransmitters—glutamic acid and GABA—and folate metabolism.
Glutamine is the preeminent amino acid in our central nervous system, and it is the starting point for production of both glutamic acid and GABA. While glutamic acid is widely known as an “excitatory” neurotransmitter that can stimulate and speed up nerve cell activity, it actually plays a much wider role in nervous system health that includes proper brain development, differentiation of nerve cells, and survival of nerve cells. By contrast, GABA (gamma-aminobutyric acid) is widely regarded as a primary inhibitory neurotransmitter that can decrease nerve activity in certain areas and help initiate nervous system balance needed to pave the way for activities like sleep. Researchers do not yet know exactly how folate metabolism is related to metabolism of either glutamic aid or GABA. But what researchers do know is that folate is a B vitamin that contains a “tail” comprised of glutamic acid molecules. In fact, this glutamic acid vitamin “tail” controls absorption of folate from our intestines up into our body.
During the past 10 years, research on the role of folate in nervous system support has greatly overlapped with folate research as it relates to support of the cardiovascular system. In fact, it might be hard to find an area of metabolic research that has generated more excitement that this overlapping area of folated-related events critical for health of our cardiovascular and nervous systems.
The overlap begins with the ability of adequate dietary folate to help keep blood levels of homocysteine in check. Homocysteine (Hcy) is a well-documented marker for cardiovascular disease that when excessive, represents a clearly increased risk for a variety of cardiovascular problems. (Hyperhomocysteinemia is the name of the condition for high Hcy in the blood.) Optimal levels of blood folate in one particular form (5-methyltetrahydrofolate, or 5-MTHF) can directly help lower Hcy levels. By helping to keep Hcy levels in check, healthy intake of folate can help lower risk of cardiovascular disease.
The benefits of folate for lowered cardiovascular risk do not stop with Hcy, however. Balanced levels of nitric oxide (NO) in the blood are equally well-established as being important for cardiovascular health. NO helps to regulate many cardiovascular functions, and appropriate levels of NO are considered protective again high blood pressure, excessive clumping of platelet cells, and other key aspects of blood flow.
Several different forms of an enzyme called nitric oxide synthase (NOS) are responsible for helping keep NO at appropriate levels in our blood. However, NOS enzymes cannot actually generate NO unless certain molecules are present to help the NOS enzymes function properly. One such molecule is BH4 (tetrahydrobiopterin). Without enough BH4 around, the NOS enzymes not only fail to produce enough NO, but they can actually worsen our cardiovascular health by producing too much of an oxygen free radical called superoxide. How is it that our bodies keep enough BH4 around? Our bodies accomplish this task with the help of an enzyme called dihydrofolate reductase (DHFR). Of course, you can easily recognize the word “folate” in the name of this enzyme, because it is the same enzyme that converts folate into its most central bioactive form in the body, called tetrahydrofolate, or THF. In other words, the same enzyme that makes sure we have enough BH4 around to keep up our nitric oxide levels also makes sure that we have the most centrally active form of folate. So you can see how our folate metabolism and our cardiovascular health are so closely connected on a metabolic level.
The key role of folate in our cardiovascular health does not stop here, however. It turns out that the overall cycle used by our body to regenerate active forms of folate—called the folate cycle—is directly tied to a central cycle in cardiovascular health called the methylation cycle. The methylation cycle is our primary way of understanding blood homocysteine levels, since this cycle continually interconverts the amino acid methionine (MET) and its fellow amino acid, homocysteine (Hcy). When our folate cycle breaks down, our methylation cycle breaks down. However, the way in which our methylation cycle breaks down is important because a breakdown in our folate cycle means a breakdown in our conversion of Hcy back into MET. In other words, a breakdown in our folate cycle means excessive accumulation of Hcy and increased risk of heart disease.
As complicated as these metabolic pathways might seem, the bottom line here is straightforward: folate is a central nutrient for cardiovascular health, and its role in cardio support is wide-ranging.
It would be wrong to leave the topic of folate and cardiovascular health without making a special note about red blood cell production. Folate is one of many nutrients necessary for the production of red blood cells. These cells carry oxygen from the lungs to other parts of the body. Along with iron, copper, vitamin B12, and vitamin B6, a deficiency of folate can impair blood cell production.
When women deficient in dietary folate become pregnant, the developing fetus is at increased risk for neural tube defects, a developmental condition that adversely affects nervous system development in the fetus. These neural tube defects are potentially devastating and can often cause loss of pregnancy.
Adverse effects on nervous system development in the fetus can occur very early in pregnancy, even before a woman is aware that she is pregnant. Because this very early occurrence of problems can be “invisible,” it is important for women to consume enough of this nutrient before they become pregnant. From a practical standpoint, this scenario means special attention to folate intake by any woman who is considering pregnancy. As noted earlier, current evidence supports a conclusion that better folate intake by women prior to pregnancy can directly reduce risk of neural tube defects in a significant way.
Some studies show lower risk of breast cancer in women with higher dietary intakes of folate, as well as decreased cancer risk at other sites in both men and women. However, the overall research on folate and cancer risk is both controversial and on the surface, sometimes contradictory, since some studies find an association between high folate intake and increased cancer risk. However, this important area of research is often confounded by the failure of studies fail to distinguish between supplemental folic acid and natural food folate.
Prevention and treatment of mental health problems—especially depression—are topics of special interest in relationship to folate intake, and we have seen some preliminary studies linking folate deficiency to increased risk of depression.