Authors: Payal Bhandari, M.D.

Contributors: Hailey Chin

Key Insights

Folate (also known as folic acid or Vitamin B9) is an important nutrient that helps the body in many ways. It plays a key role in making DNA and RNA, which are needed for cell growth and division. It also works with vitamins B12 and C to help break down food for energy, recycle amino acids, and create proteins like enzymes and hormones. Without enough folate, cells can get damaged, and the body may rely more on glucose for energy instead of breaking down proteins and fats. This can cause old cells and undigested food particles to build up in the bloodstream, making the blood thicker and raising blood pressure. This affects blood flow and can lead to inflammation, causing symptoms like tiredness, memory problems, eye disease, hair loss, skin rashes, and blood issues. If folate deficiency isn’t treated, it can lead to premature aging and chronic diseases. A healthy, plant-based diet and folate supplements can lower the risk of conditions like heart disease, diabetes, arthritis, cancer, and infections.

What is Folate? 

Serum or plasma folate levels show how much folate is in the body. Plasma homocysteine, an amino acid, is a sensitive marker of folate deficiency.

Folate, also called Vitamin B9, is a water-soluble vitamin found in plant-based foods. Folic acid is its synthetic form. Folate usually exists in the body as tetrahydrofolate (THF), which has extra glutamate residues, making it a polyglutamate. The body can’t make THF on its own.

Folate’s Role in the Body

Folate is a key nutrient that supports several important functions in the body:

1. Blood Cell Production: Folate is needed to make healthy blood cells. Without enough, red blood cells become large and immature, which means they can’t properly carry oxygen or remove carbon dioxide from the body.

2. DNA and RNA Production: Folate, along with vitamin B12, helps create DNA and RNA, which are necessary for cell growth and division.

3. Nerve Health: Folate helps form myelin, which protects nerves, and supports the creation of neurotransmitters, which allow nerve cells to communicate. A lack of folate, especially during early pregnancy, can prevent brain and spinal cord development and lead to nerve problems like numbness, tingling, and memory or mood changes.

4. Energy Production: Folate helps convert food into energy, especially when the body is under stress or injured. It’s especially important when the brain needs more energy.

5. Protein Breakdown and Recycling: Folate helps break down homocysteine and other amino acids, supporting the production of new proteins, enzymes, and hormones that the body needs for energy and growth.

Folate Absorption and Regulation 

Polyglutamate folate, from plant foods, must be broken down into smaller forms to be used by the body. This happens through several steps involving the digestive system, liver, and kidneys.

Step 1: Folate released from food
Chewing food breaks down 40% of protein, releasing folate and nitric oxide, which helps keep arteries healthy. The rest of the protein is further broken down in the stomach to release more folate.

Step 2: Folate in the small intestine
In the small intestine, stomach acidity and Vitamin C help enzymes convert folate into forms the body can absorb, like dihydrofolate and tetrahydrofolate.

Step 3: Folate enters the bloodstream and tissues
Folate is absorbed into the blood and delivered to the liver, where it’s stored or sent to the bile. Folate also moves to tissues like the brain and skin, supporting DNA, energy, and cell growth.

Step 4: Folate filtered by the kidneys
Excess folate in the blood is filtered by the kidneys and reabsorbed. If too much folate is lost in the urine, it can signal cell damage.

Figure 1: Folate metabolism starts with polyglutamate folates (a form of Vitamin B9), which are broken down by the enzyme dihydrofolate reductase (DHFR) into dihydrofolate and then tetrahydrofolate (THF). THF is further broken down by the enzyme serine hydroxymethyltransferase (SHMT) into 5, 10 Methylene THF, which is used for making nucleic acids. The enzyme methylenetetrahydrofolate reductase (MTHFR) then turns 5, 10 Methylene THF into L-Methylfolate (5-MTHF).

Clinical Significance of Low Folate Blood Levels

Low folate levels can cause genetic mutations, slow the production of new cells (especially red blood cells or RBCs), and disrupt essential body functions. RBCs are vital because they deliver oxygen, remove carbon dioxide, and provide energy for the body. Without enough RBCs (a condition called anemia), the body recruits white blood cells (WBCs), platelets, and other cells to clean up damaged tissue and stop bleeding. This repair process, called atherosclerosis, can cause inflammation.

Inflammation releases harmful proteins and reactive oxygen species (ROS), which may attack healthy tissues and lead to problems like:

1. Blood Flow Issues: Blood is redirected to injury sites, reducing circulation to other areas, like the gut. This can harm the gut lining, kill healthy bacteria, and make it harder to absorb nutrients like folate and B vitamins.

2. Gut Problems: Damage to the gut may cause “leaky gut,” bacterial imbalances, and undigested food particles entering the bloodstream.

3. Blood Pressure and Organ Damage: Inflammation can raise blood pressure, block blood flow, and harm organs.

4. Metabolism Changes: The body uses more glucose for energy, produces more ROS, and struggles to make proteins like enzymes and hormones.

5. Pathogen Activation: Dormant infections like viruses or bacteria may become active and worsen damage.

6. Chronic Diseases: If folate deficiency isn’t treated, it can lead to aging and diseases like autoimmune disorders, heart conditions, infections, cancer, and organ failure.

High-protein foods (meat, eggs, dairy, etc.) release amino acids like homocysteine (Hcy) and hydrogen sulfide (H₂S). Without enough B vitamins (found in leafy greens), Hcy and H₂S can lower antioxidant levels (like glutathione) and damage enzymes like MTHFR and CBS. This reduces amino acid recycling, raises blood acidity, and depletes folate, worsening the deficiency.

Figure 2: Eating too much protein and not enough B vitamins, like those in leafy greens, can harm how the body processes amino acids. This causes harmful buildup, slows cell growth, triggers inflammation, and leads to chronic diseases.

Folate deficiency can cause many symptoms, making it hard to diagnose. Figure 3 shows it can lead to tiredness, weak muscles, digestive problems, nerve damage, headaches, trouble thinking, mood changes, and tingling in the hands and feet. Treating the cause and taking folate supplements early can help prevent serious health problems.

Figure 3: Low folate levels harm DNA and cell growth, causing genetic changes and metabolism problems. This leads to disease, aging, and body dysfunction.

Clinical Significance of High Folate Blood Levels

Folate toxicity is rare since extra folate is removed in urine. Some people may have mild side effects like headaches, nausea, or skin rash from supplements. High folate levels in blood could mean liver problems and may cause nausea, vomiting, diarrhea, headaches, or seizures in severe cases.

Folate is stored in the liver and helps make red blood cells (RBCs). During liver stress, folate is released to repair damage, but this can cause inflammation. White blood cells (WBCs) sent to help may harm healthy tissue, cause bleeding, and make the body rely more on glucose for energy instead of fats and proteins. Taking too much folate (over 1,000 micrograms daily) or some chemotherapy drugs can change how your body uses nutrients.

Prevalence & Significance of Folate Deficiency

More than 1 in 3 people struggle to use folate and folic acid due to genetic changes, like in the MTHFR gene, which prevent the body from turning folate into its active form (5-MTHF). These people need 5-MTHF supplements and more folate-rich foods to avoid aging and chronic diseases. Folate deficiency is common in menstruating women, older adults, alcoholics, and those with gut issues or chronic health conditions.

A 2004 study found that folate deficiency increases with age, from 1 in 20 people aged 65-74 to 1 in 10 or more in those 75 and older. It can cause low energy, cognitive problems, and even mimic dementia.

Conclusion

Vitamin B9 (folate) helps protect DNA and RNA and supports the creation of new cells. Getting enough folate from food and supplements is important for good health, reducing inflammation, and preventing early aging. People at higher risk, like pregnant or breastfeeding women, older adults, and those with conditions such as autoimmune diseases, heart disease, high blood pressure, clotting issues, cancer, infections, or multi-organ problems, should take daily folic acid supplements and eat a diet rich in plant-based B vitamins.

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