DNA Methylation And COVID-19

COVID-19, Methylation Prevention, Folate And Hydroxychloroquine

Studies show methylation helps protect the cell from SARS-CoV-2 entry and prevention of COVID-19, so why did recent hydroxychloroquine research use a placebo that supports methylation? A placebo should be inert. In this article you will learn how methylation is protective against COVID-19 infection and an herb, as well as nutrients that should be studied further as protective supplements in people who might benefit from increased methylation. You will also learn why folate should not have been used as a placebo in recent research testing hydroxychloroquine as a possible preventative treatment for people exposed to COVID-19.  The ideas below are not mainstream, but need to be discussed. They would not make a pharmaceutical company big bucks though, so it is up to those on the sidelines to study these ideas.

The Recent Study On Hydroxychloroquine Should Have Used An Inert Placebo, Not Folate (B9)

A recent study tested hydroxychloroquine with folate used as a placebo to ascertain if hydroxychloroquine could prevent COVID-19 in exposed individuals. Folate supports a process in the body called methylation (supplying CH3 groups for chemical processes). Supporting methylation may help in prevention COVID-19. Decreasing methylation is integral for SARS-CoV-2 to get into the cells. Decreased CpG methylation where SARS-CoV-2 fuses/enters with the cell appears to be associated with increased symptoms and worse outcomes in COVID-19. In my opinion they should have used an inert placebo rather than folate. Why would anyone use a vitamin as a placebo for any illness anyway? Folate may be protective against COVID-19, especially in those who have MTHFR genetic variations who may need folate support to adequately recycle homocysteine and create methyl groups. Folate may also be supportive of methylation for other reasons, such as in the case of old age (also associated with decreased methylation and increased COVID-19), or people who have pre-existing health issues that might increase the need for methylation. I could argue that COVID-19 itself appears to be an illness that increases need for methylation and will do that here.

Lets Start At The Beginning

I was reading a recent study in the New England Journal of Medicine, called A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid 19. You can read the full article at this link. https://www.nejm.org/doi/full/10.1056/NEJMoa2016638. This research examined the use of hydroxychloroquine to limit symptomatic infection after SARS-CoV-2 exposure. It was a randomized, double-blind, placebo-controlled trail in the United States and Canada, that studied 821 patients who had been exposed to COVID-19, giving them either hydroxychloroquine or a placebo within 4 days of exposure. I found it fascinating that they chose to use folate as a placebo in the control group. I asked myself, why would they choose a vitamin that is known to support methylation in the body, when it appears methylation support at CpG islands might help in prevention of COVID-19 by decreasing entry of the virus into the cell?  Recently a research review called  Methylation Pathways and SARS-CoV-2 Lung Infiltration and Cell Membrane-Virus Fusion Are Both Subject to Epigenetics, was printed in the May 2020 journal, Frontiers in Cellular and Infection Microbiology. This article had reviewed many past studies related to viruses, methylation and specifically how methylation is related to SARS-CoV-2 and its fusion/entry into the cell through the angiotensin-converting enzyme 2 receptor. You can read the full article at this link. https://www.frontiersin.org/articles/10.3389/fcimb.2020.00290/full

Methylation May Be A Key Factor For SARS-CoV-2 Entry Into Cells

It turns out that methylation and perhaps enhancement of methylation may be protective from invasion of the SARS-CoV-2 virus.  For a virus to invade our cells, it needs to fuse to the cell membrane and/or move through the membrane to get inside of our cells. This allows the virus to invade our cells and hide from our immune system. This viral-cell membrane fusion is called a syncytium.  Syncytium formation is normal for coronaviruses and seen in SARS-CoV-2 specifically. It has also been noted in some other viruses. Methylation of the syncytin genes is necessary to prevent expression of syncytium-forming proteins. (Leading researchers to believe that lack of adequate methylation would increase virulence and symptoms of viruses using this method to invade cells.)

How Angiotensin Converting Enzyme 2 receptor Is Involved

SARS-CoV-2 has been shown to be much faster than SARS-CoV-1 at syncytium formation. It is thought by researchers that lack of adequate methylation in the angiotensin converting enzyme 2 receptor is a factor in the virulence of SARS-CoV-2 and cause of the cytokine storm activity. A study of 700 patients showed angiotensin-converting enzyme 2 (ACE2) was highly expressed in patients suffering severe SARS-CoV-2 symptoms when compared to controls. https://www.medrxiv.org/content/10.1101/2020.03.21.20040261v1

The Importance Of Angiotensin Converting Enzyme 2 Receptors

The ACE2 receptors are the door by which SARS-Co-V-2 appears to enter the cell. Methylation is important for gene encoding for angiotensin-converting enzyme 2. Studies show the angiotensin-converting enzyme 2 receptor to be the virus receptor in the lung epithelial cells that is the most important receptor for SARS-CoV-2 entry into cells. The production and rate of the ACE2 enzyme by its gene is under epigenetic control (this means it can be altered by the environment, food you eat, life-style habits, stress etc.) and that activity is specifically based on methylation control. (To learn more about methylation see this article) The methylation rate in the lung epithelial cells was shown to be the lowest in relation to other tissues, which suggests the ACE2 enzyme is probably highest expressed in the lungs. The ACE2 receptor is in many organs including the gut, liver, kidney, pancreas, brain and blood vessels, but it is thought to be highest in the lungs. In the lung. The extensive surface of alveolar epithelial cells might also explain the vulnerability of this organ to the consequences of virus invasion.

Factors Affecting Methylation of the ACE2 Gene

Factors Shown In Studies To Decrease Methylation And Appears To Increase Virus Entry
  • Older age compared to younger age
  • Smoker compared to non-smoker
  • Being Male compared to being female
  • Systemic lupus erythematous
Age Details

It has been shown that as one ages, there is decreased methylation of the ACE2 gene in oral and lung tissue, causing an increased expression of ACE2 in older people and may be a reason they are more susceptible to SARS-CoV-2 and other viral infections. Children have hypermethylated oral tissues and lungs with decreased ACE2 expression which should protect them.


Male gender also correlates with decreased methylation of the ACE2 gene in relation to females.


It has been proposed that the male/female difference might be due to smoking. Men in some countries are more likely to smoke than women and smoking is associated with decreased methylation and higher ACE2 gene expression compared to non-smokers, but testosterone itself is also associated with increased expression of ACE2 and furin in men.

Systemic Lupus Erythematous

Researchers find Systemic lupus erythematous patients (SLE) are more likely to develop symptoms of COVID-19 and they are found to have hypomethylation causing increased expression of the lung ACE2 protein, along with demethylation of interferon genes. This demethylation of interferon genes causes a higher expression of interferon genes and is associated with more severe SLE and the cytokine storm which is also seen in COVID-19.

Researchers Ideas Of Protective Drugs Or Supplements

  • Vitamin D
  • Quercetin
  • Curcumin (from Turmeric)
  • Deferasiorox
  • 8-hydroxyquinolones

The researchers thought vitamin D and quercetin might be helpful in decreasing symptoms of COVID-19 by inhibiting expression of ACE2 and furin, but there is only in vitro data, no clinical data. Lower vitamin D levels have been correlated with increased COVID-19 death rates in European countries. Other ideas they have for decreasing expression of ACE2 and interferon genes is curcumin (from Turmeric), deferasiorox and 8-hydroxyquinolones.

PredispositionTo Hypomethylation

Some Individuals may have a diet, lifestyle, health issues, or genetics that predisposes them to inadequate nutrients needed in methylation.

For people with MTHFR genetic variants or who otherwise need to support methylation there are a variety of nutrients, herbs and supplements that have proven useful in clinical settings and they should be considered for research. This is not something we should haphazardly guess at because hypermethylation can cause as much havoc in the body as can hypomethylation. This is something that needs to be studied however. I want to repeat that some people can be harmed by adding methylation supplements to their diet, while others can be helped, so it is not something people should consider without advice from a practitioner who is adept at nutritional support.

Nutrients/Herbs To Enhance Folate And/Or The Methionine Cycle To Produce Methyl Groups Necessary For Methylation

  • Folate (B9) - L-5-methyltetrahydrofolate
  • B12 (cobalamin)
  • B6 (pyridoxine)
  • Riboflavin (B2)
  • Trimethylglycine (betaine)
  • Choline
  • Zinc
  • Methionine – S-adenosyl methionine
  • Turmeric/Curcumin to help support methylation
Turmeric/Curcumin To Support Methylation

Curcumin has been shown to hypermethylate CpG islands in research. It is known that viral infections use epigenetic mechanisms in general and especially CpG methylation to find ways to induce syncytium development and enterocytosis or take advantage of hypomethylated cell membranes. As mentioned previously, SARS-CoV-2 uses hypomethylated membranes as cellular entry points.  I think that Turmeric and its constituent curcumin is the one herb that I would pick to research upregulation of methylation and protection from COVID-19 effects. There are other herbs that I believe are beneficial for COVID-19 in other ways.

Folate Was Not A Good Placebo To Choose

After finding the extensive amount of data showing hypomethylation makes a person more susceptible to the ravages of COVID-19, I am wondering how these researchers could have possibly chosen folate as a placebo. The data is easily accessible.  Although folate may not make a difference for everyone taking it, it seems that its beneficial support of methylation activity in some individuals would make it a bad candidate as a placebo. I don't know that without testing it as a preventative agent for COVID-19, but I think the available research supports my idea and should make us question this. Additionally, it appears that methylation support might be helpful in those who are older, male, smokers and who have lupus as well as any other situation where there is general low methylation issues at hand. Specifically, those studied in relation to COVID-19 and hypomethylation at the CpG islands of the ACE2 receptor. Studying the nutrients above and curcumin as preventatives to COVID-19 makes a lot of sense to me.

Research On Zinc and Hydroxychloroquine

There is research showing zinc and hydroxychloroquine should be used together. Several studies have shown increased intracellular zinc concentrations inhibit RNA-dependent RNA polymerase and other proteins necessary for the different phases of a viruses life cycle. Hydroxychloroquine  appears to help the zinc get inside the infected cells to destroy the virus.  In research they don't like to study more than one drug or supplement, but  many of us know that in real life synergism of nutrients and herbs are important. In this case using a drug and mineral together would have been a better idea probably, rather than just the drug. By the way, hydroxychloroquine was based on quinine which isolated from Cinchona bark. Something that gets forgotten is that many drugs are based on natural products. Just like hydroxychloroquine, quinine can cause side effects.

More Research Needed On ACE2

There have been studies showing differences in ACE2 expression correlating to sex, age, race and disease processes. There is so much we don't know about gene expression of ACE2. Learning what can increase or decrease it will be helpful in defending ourselves against COVID-19.

Just Thoughts And Not Facts

These ideas about increasing methylation are just my opinion, and although there is support from a variety of studies that some of them do support methylation at CpG islands, none of this has been studied clinically for COVID-19 prevention/treatment. Therefore do not assume overall support of methylation will prevent COVID-19. I am not assuming that. Nutrients and herbs need to be studied to see if they specifically increase methylation at the CpG islands and/or if these nutrients herbs are preventative in people exposed to SARS-CoV-2. I am putting fourth the idea that they might and look forward to further research on this matter.

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