Reducing folate intake as you age may lead to a healthier metabolism and body weight—if you’re a mouse, at least.

In a July study published in Life Science Alliance, a folate- and choline-restricted diet increased metabolic rates in middle-aged male mice. In females, the diet resulted in better “metabolic plasticity,” or the flexibility to switch between burning carbohydrates and fat for energy. All the mice maintained their weight and body composition better than the group consuming normal folate levels.

The study’s authors concluded that “a lower folate intake later in life may result in healthier aging.”

However, that doesn’t appear to be the whole story for humans. Folate is critical for several essential metabolic and cellular processes, and when it comes to aging, how your body handles folate may be just as important as how much you get from food and supplements.

Folate for Heart Health

Also called vitamin B9, folate is a water-soluble vitamin that plays a key role in DNA synthesis and cell division. It acts as a coenzyme to support reactions that build DNA and proteins during cell division, and it’s required for red blood cell formation.

Folate is also critical for keeping levels of an amino acid called homocysteine in check. Your body naturally creates homocysteine while metabolizing the amino acid methionine, but having too much of it can negatively affect cardiovascular health. Folate helps prevent homocysteine buildup by assisting in its conversion back into methionine.

Folate Sources

You can get folate from a variety of foods, but Dr. Chris Miller of Love.Life Telehealth cites leafy greens as the best source.

“Leafy greens are No. 1 ... including romaine,” she told The Epoch Times. “People are like, ‘Oh, there’s no benefits to romaine’ because they’re trying to eat the dark leafy greens. But all lettuces are going to have folate. So even butter lettuce, the type we don’t usually want to eat very much, is going to have folate.”

Other sources of folate include beans, citrus fruit, asparagus, eggs, avocados, some nuts and seeds, organ meats such as liver, and cruciferous vegetables such as broccoli. These foods contain folate in its natural form. The synthetic form—folic acid—is added to foods such as cereal, bread, rice, pasta, and some types of flour.

Folic acid is considered the better form because naturally occurring folate is unstable and can be destroyed by cooking or processing.

Chris Mohr, registered dietitian and fitness and nutrition adviser for Fortune Recommends, told The Epoch Times: “Synthetic folic acid is ideal for fortification. It is more bio-available than natural folate and, unlike natural folate, is stable in food, even during cooking.”

Folate Metabolism

When you supplement with folic acid or eat folate-fortified foods, your body must convert the vitamin to its active form, 5-methyltetrahydrofolate (5-MTHF), before it can be used. This conversion happens through a multi-step process that occurs in the liver:

• An enzyme called dihydrofolate reductase (DHFR) turns folic acid into dihydrofolate.
• Dihydrofolate becomes 5,10-methylenetetrahydrofolate through the action of the methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) enzyme.
• The methylenetetrahydrofolate reductase (MTHFR) enzyme turns 5,10-methylenetetrahydrofolate into 5-MTHF.

Both DHFR and MTHFR can be rate-limiting, meaning they control how quickly folic acid converts to 5-MTHF. The DHFR enzyme has weak activity in humans and can be overrun by high doses of folic acid. Moreover, some people have genetic variations that affect MTHFR function. Excessive folic acid intake may also inhibit MTHFR. These disruptions can cause unmetabolized folic acid to enter the bloodstream, which may have detrimental effects.

Naturally occurring folate bypasses this process, converts to 5-MTHF in the gut, and enters the bloodstream in its active form.

MTHFR Explained

Metabolizing folate can be particularly challenging for people who have a mutation in a gene that regulates the MTHFR enzyme. MTHFR plays a key role in methylation, a process essential for folate conversion. In some cases, problems with methylation that result from MTHFR gene mutations can lead to folate deficiency, even when intake is adequate.

Miller says that, although most people don’t need to think about MTHFR mutations, she has seen some patients who experience chronic symptoms such as mental health issues, autoimmune reactions, and gastrointestinal disturbances. This may be due to the role folate plays in the brain, immune system, and gut.

Active folate is required to synthesize neurotransmitters and keep homocysteine in check. Excess homocysteine may lead to oxidative stress, which can damage neurons and affect mood, and inadequate neurotransmitter production can contribute to depression.

In the digestive tract, folate plays a role in regulating both innate and adaptive immunity, including preventing the death of the regulatory T-cells that support balanced immune reactions. Folate deficiencies can disrupt cell division in the gastrointestinal tract and trigger symptoms such as diarrhea.

MTHFR also plays a role in methylation reactions. According to Miller, poor methylation can increase oxidative stress, cause tissue damage, and “trigger or exacerbate autoimmune conditions.” Inflammation resulting from impaired methylation can damage the gut lining and cause additional gastrointestinal issues.

Supplementing with the active form of folate—which is already methylated and ready for the body to use—may help relieve these symptoms in people whose health doesn’t improve with dietary change.

Folate and Aging

Whether or not you have an MTHFR mutation, age-related changes such as loss of enzyme function or damage to intestinal microvilli can inhibit your ability to absorb folate.

“[Folate is] absorbed in the small intestine, and the folate has to have enzymes—several of them,” Miller said. “These enzymes have to be active, and the small intestine has to absorb it. So, as people get older, they don’t absorb as well.”

These changes may mean you need more than the 400 micrograms per day recommended by the National Academies of Sciences, Engineering, and Medicine’s Food and Nutrition Board. However, research from the past two decades has begun to show that consuming excessive folic acid from supplements or fortified foods may lead to health problems as you age.

Risks of Too Much Folate

High folic acid intake has been associated with detrimental health effects, such as reduced immune activity and increased cancer risk. Pregnant women who take too much folate may increase their unborn children’s risk of developing inflammatory diseases such as atopic dermatitis. In older people with B-12 deficiency, supplementing with folate may impact cognitive health and performance.

Results regarding the risks of excess folic acid are mixed. A 2017 analysis of folic acid safety concluded that evidence showing a connection between high intake and disease outcomes is insufficient and highlighted several studies showing that high intakes may actually be protective. For example, some studies show that higher intake may protect against conditions such as stroke and cancer, and folic acid supplements may protect against cognitive problems when B-12 levels are adequate.

Conflicting study results may be due to factors such as variable B-12 absorption between individuals and differences in how researchers define “high” folic acid intake.

A Natural Fix

To limit potential negative effects, the Food and Nutrition Board sets the upper intake limit for folic acid from supplements and fortified foods at 1,000 micrograms per day. But filling your plate with greens, beans, and other foods that contain natural folate should be safe.

“There is no upper limit for folate intake from natural food sources,” Mohr said, “as there is no evidence of problems from consuming folate in its natural form.”

He advises “regularly eating fruits, legumes, nuts, and seeds throughout the week” to maintain healthy folate levels. Miller also recommends including four cups of raw leafy greens daily.

Despite the results of the Life Science Alliance study, human research doesn’t suggest benefits from a one-size-fits-all approach to folate intake. The authors note that differences in blood folate levels and DHFR activity between mice and people could mean that mice react differently to low-folate diets. More research is needed to determine how folate influences human health later in life.