Vitamin B12 and Folate: Understanding the Connection

Folate and B12 are B vitamins that play critical biological roles in energy metabolism, homocysteine conversion, brain health, and more.

But while they have many roles on their own, B12 and folate are both essential for red blood cell production, DNA synthesis, and cardiovascular health.

Chances are you’ve heard someone tell you that you must consume enough B12 and folate. While both belong to the family of B vitamins, they are essential nutrients that have individual roles but also some that overlap.

Both are found in various foods, making getting enough relatively simple. Few young people have a deficiency, but it’s estimated that up to 20% of adults over 60 are low in vitamin B12, and up to 20% of the U.S. population is folate-deficient ^{1, 2}.

But why do you need these essential nutrients? And how are they involved? In this article, we’ll dive into vitamin B12 and folate’s details and how they’re related.

Let’s get started.

What’s The Link Between Vitamin B12 and Folate?

Often, you hear about vitamin B12 and folate together—and it’s not just because they’re both B vitamins. The interrelationship between these two vitamins is as follows:

1. Homocysteine metabolism

Homocysteine is a sulfur amino acid, and high plasma levels indicate vitamin B12 and folate deficiencies ³. On top of being a risk factor for pregnancy complications, neural tube defects, mental disorders, and cognitive impairment, it’s also a strong risk factor for atherosclerotic vascular diseases, which is why conversion is critical. This conversion takes place in two steps:

A. Remethylation to methionine, which depends on folate and vitamin B12B. Transsulfuration to cystathionine, which requires pyridoxal-5'-phosphate (vitamin B6)

If B12 and folate aren’t available to convert homocysteine into methionine, we see a buildup in the blood and hyperhomocysteinemia ³.

2. Erythropoiesis

Erythropoiesis is the process whereby new erythrocytes (immature red blood cells) are produced. Folate, vitamin B12, and iron are all essential during this process, especially during their differentiation phase.

A deficiency of folate or vitamin B12 can interfere with this process and produce abnormally large red blood cells, also known as megaloblastic anemia ⁴.

We talk about anemia with respect to the “methyl-folate trap.” Because vitamin B12 isn’t available for converting 5-methyl tetrahydrofolate back into folate, folate becomes “trapped” in the form of 5-methyl tetrahydrofolate.

And because folate is required to produce red blood cells and DNA, insufficient availability leads to the production of red blood cells that don’t fully mature and stay large.

The Health Benefits Of Vitamin B12

Unlike specific vitamins that can be synthesized in the body, vitamin B12 isn’t one. It’s a water-soluble vitamin found in high concentrations in animal products.

It plays crucial roles in many biological processes ranging from erythropoiesis and DNA synthesis to brain development and nervous system function. It’s also required as a co-factor for specific enzymes involved in synthesizing fatty acids and myelin ⁵.

Getting enough B12 through diet isn’t difficult for most people, but it can be tricky for those who don’t consume animal products. But that’s not the only issue.

For B12 to be absorbed from food, you need sufficient amounts of a protein called intrinsic factor. It’s a glycoprotein produced by parietal cells in the stomach and is required to absorb vitamin B12 in the latter part of the intestine ⁶.

And for IF to be activated, you need sufficient amounts of stomach acid. Low stomach acid and dietary insufficiency are two primary risk factors for a vitamin B12 deficiency.

So, why is B12 so essential for optimal health and well-being? Here are five reasons:

1. Supports red blood cell formation: Adequate levels of B12 are essential for erythropoiesis. Erythroblasts, also known as immature red blood cells, require folate and vitamin B12 for proliferation during their differentiation phase. Low vitamin levels inhibit purine and thymidylate synthesis, impairing DNA synthesis, and resulting in erythroblast apoptosis (death) ⁷. When a vitamin B12 deficiency ensues, the result is larger, oval-shaped red blood cells that can’t move from the bone marrow into the bloodstream.
2. May improve bone health: Vitamin B12 may not be the first vitamin you think of concerning bone health, but it’s important because of its link to homocysteine metabolism, and therefore, may have protective benefits for bone health and reduce the risk of osteoporosis or hip fractures ⁸. The mechanism behind vitamin B12’s protective effects aren’t clear. Still, research shows that it’s involved in osteoblast proliferation and formation, and a deficiency can increase osteoclast activity, potentially via its influence on increasing methylmalonic acid (MMA) and homocysteine levels ⁹.
3. Protects the heart: High homocysteine is a risk factor in several cardiovascular events because it has adverse consequences on vascular endothelium and smooth muscle cells, which can lead to structural arteries in the arteries and their function ¹⁰. Because B12 regulates homocysteine levels, studies find that a higher intake of B12 can reduce elevated homocysteine and decrease your risk of heart disease and stroke ¹¹.
4. May improve mood: Feeling a little blue? Some B12 might help! The involvement of B12 and mood aren’t completely clear, but studies find that low B12 is linked to an increased risk of depression. Some studies suggest it may be involved in the synthesis and metabolism of serotonin and dopamine, two brain chemicals involved in regulating mood, emotions, and sleep ¹². Some research finds that people who are low in B12 are twice as likely to develop depression than people with normal B12 levels ¹³.
5. Supports energy production: Because of vitamin B12’s role in red blood cell formation, the inability of irregularly-shaped red blood cells to move from the bone marrow into the bloodstream can lead to anemia, characterized by symptoms like fatigue and weakness.

The Health Benefits Of Folate

Folate, also known as vitamin B9, is another water-soluble vitamin essential to optimal health and well-being. Although you don’t need folate in large quantities, it’s necessary for a wide range of functions, including ^14-17:

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• DNA and RNA synthesis, repair, and methylation
• Cell division
• Homocysteine
• Red blood cell maturation

But why is folate so critical? You may have heard about its role in pregnancy, but folate functions in several coenzyme forms in several biochemical reactions. These folate-dependent metabolic processes depend on levels of folate but also levels of vitamins B6 and B12 ¹⁸.

Keep in mind that folate and folic acid aren’t the same things. Folate is the natural form of the vitamin that’s converted to the active form, 5-methyltetrahydrofolate (5-MTHF), before entering systemic circulation ¹⁹. Folic acid is the synthetic form found in supplements and many fortified foods.

Not all folic acid is converted to 5-MTHF, and what is undergoes a relatively slow and inefficient conversion process, meaning that even small doses may not be fully metabolized before the next dose enters the blood.

Here are five reasons why folate is essential:

1. Supports DNA and RNA biosynthesis: Folates’ role in DNA and RNA production and methylation is one of its most well-known roles. Because all mammals rely on DNA methylation for normal development and function, alterations to folate intake can interfere with the process, inhibit normal growth and development, and potentially result in chromosomal abnormalities ²⁰.
2. Prevents developmental abnormalities: A healthy pregnancy (and a healthy mom pre-conception) depends heavily on adequate folate intake because of its role in developing the brain and spinal cord. It’s essential to prevent neural tube defects in the fetus, which develop from the failure of the embryonic neural tube to close between 21-27 days after conception ²¹.
3. Support amino acid conversion: As with vitamin B12, folate is also required for homocysteine metabolism; they are both essential for converting homocysteine to methionine. Under normal circumstances, homocysteine conversion is mediated by the donation of a methyl group from 5-MTHF, the active form of folate, and this conversion also vitamin B12 as a coenzyme ²². A B12 or folate deficiency interferes with homocysteine conversion and can lead to a buildup in the blood, which is a significant risk factor for cardiovascular events.
4. Increases erythropoiesis: Folate and vitamin B12 are both involved in producing red blood cells. As mentioned before, erythroblasts require folate and B12 during the proliferation phase of differentiation, and a deficiency of either leads to abnormal red blood cells, which can end with anemia. If this is the case, you’re likely left dealing with symptoms like fatigue, low energy, muscle weakness, and paraesthesia.
5. Enhances brain health: Looking for sharper brain function? Consider folate. Research shows that folate deficiency—or even low levels—is linked to reduced brain function and a higher risk of cognitive impairment ^{23, 24}. A 2019 study published in the European Journal of Nutrition found that 400 mcg of folic acid supplemented daily for two weeks in adults with mild cognitive impairment led to improvements in various measures of brain function and reduced blood levels of proteins involved in the development and progression of Alzheimer’s disease ²⁵.

Final Thoughts

There’s no denying that vitamin B12 and folate are essential components of a healthy diet, and getting enough of both is critical to many important biological processes in the body.

For anyone following a plant-based diet, supplementation may be advised to avoid a deficiency—but ensure you’re investing in a quality supplement like Performance Lab NutriGenesis Multi. It’s a pure and potent ultramodern multivitamin designed specifically for men’s and women’s needs.

Supplying over 100% RDA of 17+ essential vitamins and minerals in optimal dosage and preferred forms, with Multi, you can feel confident that your body can use what you’re taking.