Folate Part I: Folate and Methylation

How does B9 affect circadian rhythms?

Care providers recommend folic acid to all women who want to conceive. At the same time, unmetabolized synthetic folic acid is associated with cancer, depression and cognitive impairment¹. What gives?

Folic acid is one of the most controversial prenatal supplements. There are two main schools of thought. Since this topic wraps around to circadian rhythms and the light/dark cycle, I wanted to share it with you.

Here are two ways to think about folic acid supplementation:

1. Populations focus. In past studies, folic acid supplementation reduced rates of neural tube defects. (And other issues such as autism, depression, cancers, and dementia).

2. Individuals focus. Between individuals, folic acid metabolism can vary. For some, it can be like throwing gasoline on a grease fire of inflammation (look up homocysteine if interested in why).

This divergence in thinking is causing the conflicting advice about folic acid supplementation.

In today's post, I thought I'd dig into the circadian health aspects of methylation. Then, I'll talk about dietary folic acid, folate, and methylfolate. Finally, I'll share how the environment impacts our ability to use folates at all. Enjoy!

What is methylation?

In chemical terms, methylation is adding a methyl group to another molecule. This process of adding methyl groups is one of the ways we look at circadian rhythms at the cellular level. According to Fustin, et al., "methylation is a universal regulator of rhythmicity.²" In labs, scientists look at genes and count how many cites have a methyl group. This number usually shows a daily variation, with more methylation showing at night. Looking at methylation levels can show how in-rhythm (or not) things are at the level of DNA. It is part of the study of genes known as epigenetics.

Here's a quick description of methylation in the context of genetics and epigenetics³:

Genetics is the study of heritable changes in gene activity or function due to the direct alteration of the DNA sequence... In contrast, epigenetics is the study of heritable changes in gene activity or function that is not associated with any change of the DNA sequence itself. Although virtually all cells in an organism contain the same genetic information, not all genes are expressed simultaneously by all cell types. In a broader sense, epigenetic mechanisms mediate the diversified gene expression profiles in a variety of cells and tissues in multicellular organisms... It is now well recognized that DNA methylation, in concert with other regulators, is a major epigenetic factor influencing gene activities.

Source: DNA Methylation and Its Basic Function by Lisa Moore, Thuc Le and Guoping Fan (2013)

The folate cycle (summarized in the grapgic below as "THF"), connects with the methionine cycle to create “the universal methyl donor for methylation reactions.⁴”

This is one of many reasons we need a consistent supply of folates and folate cofactors* throughout our bodies⁵.

How do we get folate? And what's up with all the different types?

I promised to talk about folic acid, folate, and methylfolate, so here goes. These nutrients are part of a family that fit into the folate cycle.

Graphic of the methylation and methionine cycles and cofactors.

As you can see highlighted in grey, there are many cofactors! Enzymes (highlighted in green) also come into play with these cycles. Folic acid, folate, and methylfolate each have a unique place in this cycle. There are other types of folates as well, and other cycles that in turn depend on the folate cycle.

Graphic showing 6 specific cycles that require folates.

As you can see, this idea that ‘we need folates’ just keeps getting bigger and bigger!

Genetic heritage and the availability of other nutritional cofactors and enzymes and the health of all six of these major cellular cycles all matter.

To get back with just the folate aspect, it turns out gut health and probiotic populations may make the biggest difference—more so than actual dietary intake.

(In fact, the near-impossibility of eating the supposed recommended daily intake (RDI) of folate in pregnancy is a major factor driving my interest in this topic.)

Here’s the saving grace: there are over 500 species of bacteria that create folates, with Bifidobacterium (especially B. adolescentis and B. pseudocatenulatum) and Lactobacillus plantarum being the most popular and well-studied. Many probiotics involved with dairy fermentation also produce folates. Indeed, according to Shulpekova, et al., fermentation within our own bodies may actually be the most significant source of folates⁶:

"Pool of folates produced by the colonic bacteria typically exceeds their dietary intake... The rate of colonic absorption is relatively low. However, its real contribution may be rather significant due to long transit time and abundant folate production."

Source: The Concept of Folic Acid in Health and Disease by Shulpekova, et al. (2021)

Here are the top ten unfortified food sources of folate (according to the NIH):

1. Beef liver, braised

2. Spinach, boiled

3. Black-eyed peas, boiled

4. Rice, white, medium-grain, cooked

5. Asparagus, boiled

6. Brussels sprouts, frozen, boiled

7. Lettuce, romaine, shredded

8. Avocado, raw, sliced

9. Spinach, raw

10. Broccoli, chopped, frozen, cooked

Keep in mind excessive heat, PH, and even over-exposure to air can degrade folate significantly (or even entirely) between the time a food is harvested and makes it to our plate⁷. It turns out, the sensitivity of folate to heat and oxidation is true even of folates inside our body! So just eating the RDI of folates is not enough to guarantee an adequate supply of folates within our cells.

How does the environment control internal folate levels?

Here’s where the folates question starts to get really big. What if we have it all wrong with the hypothesis that skin pigmentation exists to combat UV damage? Think about it: fatal UV damage doesn’t manifest until AFTER the childbearing years. But there is something to do with pigmentation and latitude...

It turns out, the answer may lie with folate and Vitamin D.

Here’s what researchers from the Arizona Cancer Center have to say⁸:

The original hypothesis that dark skin pigmentation arose to protect against skin cancer induced by UV exposure does not account for selective reproductive pressure as fatal repercussions of skin cancers tend to develop after reproductive age. In this reasoning, the adaptive response of skin pigmentation toward the adequate protection or production of micronutrients which play key roles in the success of the reproductive process has gained much credibility. The evolution of dark skin to protect against folate photo-degradation serves a direct reproductive influence as folate is now known to be essential for fetal development and fertility. The attenuation of skin pigment levels to allow for adequate vitamin D production also serves a direct reproductive influence in fetal bone development and maternal bone health. This model in which skin pigmentation balances availability of essential micronutrients is of much interest as shifting world populations result in many people residing in areas of UV exposure that are significantly different from those to which their skin tone has been adapted.

Source: Folate in Skin Cancer Prevention by J.D. Williams, Elaine L. Jacobson, H. Kim, M. Kim, and M.K. Jacobson (2012)

Pretty interesting stuff! 

To recap, we get folate from our microbiome primarily, and also from our diet in low to moderate amounts. That folate gets distributed throughout the body to support chemical processes within cells. Then, UV—necessary for Vitamin D and so much more (review U Need UV in case you missed it)—degrades folate. Is this a health paradox!? No! What this means is we need a balance of sunshine and darkness for optimal health because the body actually uses folate at night.

In the words of Dr. Jack Kruse:

The absence of blue light at night is critical light effect needed to catalyze the solid state conversion of serotonin by using the process of methylation. Methylation during darkness mediates circadian clock plasticity both in the SCN and in the peripheral clocks. This solid state biochemical process requires a large exclusion zone (EZ) and the presence of vitamin B12 and folate. B12 is made in the liver under the presence of SOLAR daylight. Folate, on the other hand, is destroyed by full spectrum sunlight and it is produced under darkness when blue light is ABSENT. These are the two chemical arms that tell the quantum clinician if a patient is solar deficient and/or blue light toxic. Obesity and T2D are two such quantum diseases that manifest when this situation occurs in humans. B12 and Vitamin D3 are linked to specific sunlight frequencies and this is why pernicious anemia is associated with a lack of sun. In fact, most anemias are related to a lack of proper solar exposure.

Source: Dr. Jack Kruse Forum Post (2016)

TLDR:

To optimize folate, you need a strong microbiome, folate cofactors*, and to live under a natural (sun)light/darkness cycle.

And it seems that, at least when it comes to folate, you may choose to eat, or not to eat, the spinach.

*Sources vary on which cofactors of folate they mention, but here are the ones I have found so far: DHA, Magnesium, Zinc, D3, B12, B6, B3, B2, Choline, and Serine.

Head to Folate Part II: Folate Cofactors to learn more about these nutrients and how to get them from your diet:

Folate Part II: Folate Cofactors

1. Arya, S., Pavitra, K. (2012). Folate: sources, bioavailability and production.

2. Fustin, J., Ye, S., Rakers, C., Kaneko, K., et al. (2020). Methylation deficiency disrupts biological rhythms from bacteria to humans.

3. Moore, L., Le, T., and Fan, G. (2013). DNA Methylation and Its Basic Function.

4. Mentch, S. and Locasale, J. (2016). One Carbon Metabolism and Epigenetics: Understanding the Specificity.

5. Niculescu, M. and Zeisel, S. (2002). Diet, Methyl Donors and DNA Methylation: Interactions between Dietary Folate, Methionine and Choline.

6. Shulpekova, Y., Nechaev, V., Kardasheva, S., et al. (2021). The Concept of Folic Acid in Health and Disease.

7. Witthoft, C., Forsskn, K., Johannesson, L., and Jagerstad, M. (1999). Folates - food sources, analyses, retention and bioavailability.

8. Williams, J.D., Jacobson, E., Kim, H., Kim, M., and Jacobson, M.K. (2012). Folate in Skin Cancer Prevention.