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Did you know that MTHFR is the most studied gene in nutrigenomics? In fact, the methylation pathway is involved in the conversion of homocysteine to methionine, using folate. It is also involved in the processing of sulfur-containing amino acids and the production of
glutathione, our major detoxifying enzyme. DNA methylation modifies the human genome, affects aging, defines our “epigenetic clock” and can influence many diseases. Read more below to learn more.

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What Is Methylation? methylation and demethylation
I recently discovered that I am homozygous for the C677T — this variation is present in only 4% of the population. And with this mutation, the enzyme function could be reduced by about 70%. It might explain some of the health issues that I have dealt with.
But what exactly is methylation?
Methylation in humans affects the cytosine (C) nucleotide. It is the process by which a methyl group (a carbon atom with 3 hydrogen atoms attached to it) connects to the cytosine nucleotides (R).
The steps to converting folate to MTHF or methyl tetrahydrofolate involves many enzymes, including MTHFR.
  • The methylation cycle starts with homocysteine
  • One of the molecules affected in this pathway is involved in making DNA.
  • Another, MTR or methionine synthase, converts homocysteine to methionine. It needs vitamin B12 and 5-MTHF to function.
  • SAM has a methyl group attached to it, which it can “give” to our DNA, causing DNA methylation.
  • The end result of the methylation cycle is methionine, but also produces other compounds important for antioxidant defense and affects folate metabolism
We often hear about ways to “turn on”or “turn off” genes, but the biochemical basis on it is methylation: adding a methyl group is one way of turning on and off a gene. In normal cells, methylation ensures this proper gene activation and silencing. DNA methylation causes a crucial modification to the genome that is involved in regulating many cellular processes. These processes include chromosome structure and stability, DNA transcription, and embryonic development (R, R).

But if the methylations cycle is less efficient — like if the activity of your MTHFR is reduced — homocysteine can build up because not enough of it is being converted to methionine. High homocysteine levels are a big risk factor for many diseases — from inflammation and heart disease, to diabetes, autoimmune diseases (like psoriasis), neurological issues, cancer, and others [R].

If you’re curious to read more, download the Methylation Bonus that goes in-depth about the science, specific SNPs to look out for, and how I was able to overcome my MTHFR issues.

Get the free Methylation Special Report

Types of Methylation

Methylation is the basis of epigenetics, the study of how the environment affects our genes. Our environment, our lifestyle, and diet are all factors that can turn genes on or off. The patterns of methylation and demethylation presented here can have an impact of health, aging, and chronic disease like cancer [R].

1) DNA Hypermethylation


A healthy body has a certain level of methylation. Irregular and over-methylated DNA can change a gene, preventing it from producing what it’s meant to. Changes in the placement of methyl groups can cause diseases (R).

Some researchers have even used the amount of methylation in certain genes as a biological clock, as it occurs in individual genes is proportional to age. The implications include, but are not limited to:

  • Causes cancer
  • Lowers immune system function
  • Damages brain health
  • Lowers energy and exercise
  • Quickens aging

It can inactivate certain tumor-suppressor genes and stop the expression of mRNAs that play a role in tumor suppression (R).

Additionally, external, environmental factors can alter methylation. In other words, while abnormal methylation in DNA can replicate itself and be passed down, this balance can also be altered by everything around us (R).

2) DNA Hypomethylation

Too little of methylation can also be harmful.

shutterstock_395448409 cell

If there is insufficient methylation in the body, it can cause genomic instability and cell transformation (R).

And although hypermethylation was thought to be more common in cancers, cancers seem to equally have hypomethylation. Hypomethylation can be beneficial for cancer short-term, but it may also speed up cancer growth (R).

This methylation in cancer has been described as “too much, but too little”. In cancer, some parts of the DNA are overmethylated, and other parts undermethylated, leading to a complete dysbalance of the normal methylation cycle (R).

And aside from cancer, hypomethylation may also contribute to inflammation (leading to atherosclerosis) and autoimmune diseases, such as lupus, multiple sclerosis (R).

3) DNA Demethylation


DNA demethylation can also play a role in the formation of tumors (R).

But during embryo development, this process is crucial. Scientists have long struggled to understand how complex biochemical messages are communicated in the embryo to enable identical stem cells to develop into specialized cells, tissues, and organs. Demethylation happens in early embryos and is essential for stem cells to be able to differentiate into different cell types. Parts of DNA are turned on or off,  and then modified via demethylation again for healthy development to take place (R).

Demethylation removes the modification of the nucleotides from DNA (R).


Too Much or Too Little Methylation?

DNA methylation

Although over- and undermethylation can both be harmful, it’s important to consider which genes are being “turned on or off”. Activating or deactivating some key regions can have the most serious health complications (such as hypomethylation of the so-called repeat sequences in cancer) (R).

  • The most striking feature of vertebrate DNA methylation patterns is the presence of CpG islands, that is, unmethylated GC-rich regions that possess high relative densities of CpG (R).
  • These CpG islands are prone to progressive methylation in certain tissues during aging or in disease(R).
  • And while these CpG islands are being hypermethylated, the rest of the DNA is being hypomethylated (such as LINE-1 and Alu repeat regions), especially in cancer, but also with aging (R, R).
  • Cytosine deaminases carry out demethylation, converting 5mC to thymine, followed by T-G mismatch repair that specifically replaces thymine with cytosine (R).
  • TET family hydroxylases oxidizing 5mC may also participate in active DNA demethylation (R).
  • Either transcription persists leading to restoration of the unmethylated CpG island flanked by methylated non-island-flanking DNA, or other mechanisms extinguish transcription in the embryo and this invites de novo methylation of the CpG island and its flanks (R).

Methylation And Ageing: the “Epigenetic Clock”


Image taken from Meaghan J. Jones et al

Methylation is not a black-or-white phenomenon. It’s not symmetrical in any way. And it’s not just a matter of if your DNA is more or less methylated, but how. It turns out that methylation increases during childhood, but most of the DNA is being methylated at that time. As we age, just the specific regions of DNA, the CpG islands mentioned above, become overmethylated, while the rest of the DNA is undermethylated. This is the hallmark of aging (R).

Based on the pattern of CpG methylation, scientists can now predict someone’s age. This is called the “epigenetic clock” — a biomarker of aging — the specific methylation pattern of aging common to most people that tells us about our “functional age”. But there is also a “drift” in each individual, a pattern slightly different in each person from the general population, called the “epigenetic drift” that is still being explored (R).

Basically, based on your DNA methylation, scientists might be able to tell you your “epigenetic age” and compare it to your actual age. Based on this, you could be epigenetically younger or older. And if you’re epigenetically older, then this points to a greater chance of health problems (R).

Health Tools I Wish I Had When I Was Sick

At SelfHacked, it’s our goal to offer our readers all the tools possible to get optimally healthy. When I was struggling with chronic health issues I felt stuck because I didn’t have any tools to help me get better. I had to spend literally thousands of hours trying to read through studies on pubmed to figure out how the body worked and how to fix it.

That’s why I decided to create tools that will help others cut down the guesswork:

  • Lab Test Analyzer – a software tool that will analyze your labs and tell you what the optimal values are for each marker — as well as provide you with actionable tips and personalized health and lifestyle recommendations to help you get there.
  • SelfDecode – a software tool that will help you analyze your genetic data from companies such as 23andme and ancestry. You will learn how your health is being impacted by your genes, and how to use this knowledge to your advantage.
  • SelfHacked Secrets – an ebook where we examine and explain the biggest overlooked environmental factors that cause disease. This ebook is a great place to start your journey if you want to learn the essential steps to optimizing your health.
  • SelfHacked Elimination Diet course – a video course that will help you figure out which diet works best for you
  • Selfhacked Inflammation course – a video course on inflammation and how to bring it down
  • Biohacking insomnia – an ebook on how to get great sleep
  • Lectin Avoidance Cookbook – an e-cookbook for people with food sensitivities
  • BrainGauge – a device that detects subtle brain changes and allows you to test what’s working for you
  • SelfHacked VIP – an area where you can ask me (Joe) questions about health topics

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The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.


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  • Zoltan

    And what to do with? If my methylation doesn’t works well?! How to fix it?

  • Natcha

    Effects of methylation could be gene-specific. You might just want to have a post about epigenetics or epigenetic modifications overall, but there are so many details that are harder for most readers to understand if most of them are trying to synthesize it into actionable steps. Also, there are also methylations of neurotransmitters and other gene products that need to be taken into account.

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