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Methylation – How Does It Affect Our Health & Aging?

Written by Carlos Tello, PhD (Molecular Biology) | Last updated:
Puya Yazdi
Medically reviewed by
Puya Yazdi, MD | Written by Carlos Tello, PhD (Molecular Biology) | Last updated:

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 antioxidant. DNA methylation modifies the human genome and can influence aging and many diseases. Read below to learn more.

What 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) is bound to the cytosine nucleotides [1].

MTHFR, the most widely-studied gene in nutrigenomics is a key player in this process. People with two copies of the C677T variant (only 4% of the population) produce an enzyme whose activity is reduced by about 70% [2].

The steps to converting folate to MTHF or methyltetrahydrofolate 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 one, MTR or methionine synthase, converts homocysteine to methionine. It needs vitamin B12 and 5-MTHF to function.
  • SAM-e has a methyl group attached to it, which it can “pass” to our DNA, causing DNA methylation.
  • The end result of the methylation cycle is methionine, but it also produces other compounds important for antioxidant defense such as glutathione and affects folate metabolism.

We often hear about ways to turn “on” or “off” genes, but not about 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 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 [1, 3].

But if the methylation cycle is less efficient – like if the activity of 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 [2].

Types of Methylation

Methylation is the basis of epigenetics, the study of how the environment affects our genes. Our environment, 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 on health, aging, and chronic diseases like cancer [4].

Although over- and under-methylation can both be harmful, its 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) [5].

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 its meant to. Changes in the placement of methyl groups can cause diseases [6].

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

  • Causing cancer
  • Lowering immune system function
  • Damaging brain health
  • Lowering energy and exercise
  • Quickening aging

It can inactivate and reduce the expression of certain tumor-suppressor genes [3].

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 [6].

2) DNA Hypomethylation

Too little methylation can also be harmful.

If there is insufficient methylation in the body, it can cause genomic instability and cell transformation [3].

And although hypermethylation was thought to be more common in cancers, more recent research has revealed that hypomethylation also plays a role in these conditions. Hypomethylation can be beneficial for cancer short-term, but it may also speed up cancer growth [7].

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 imbalance of the normal methylation cycle [8].

And aside from cancer, hypomethylation may also contribute to inflammation, leading to atherosclerosis and autoimmune diseases such as lupus and multiple sclerosis [5].

3) DNA Demethylation

DNA demethylation can also play a role in the formation of tumors [9].

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 differentiate into specific cell types. DNA regions are turned on or off, and then modified via demethylation again for healthy development to take place [10].

Demethylation removes the modification of DNA nucleotides [6].

Methylation And Aging: the “Epigenetic Clock”

Methylation is not a black-or-white, symmetrical phenomenon. And it’s not just a matter of whether your DNA is more or less methylated, but how. It turns out that methylation increases during childhood, when most of this process takes place. As we age, just specific regions of DNA, the CpG islands, become overmethylated while the rest is undermethylated. This is the hallmark of aging [11].

Based on the pattern of CpG methylation, scientists can now predict someone’s age. This is called the “epigenetic clock” – a biomarker of aging based on a specific progressive methylation pattern common to most people that tells us about our “functional age”. But there is also a “drift” in each individual, a pattern slightly different from the general population in each person called the “epigenetic drift”, that is still being explored [11].

Basically, based on your DNA methylation pattern, 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, this may point to a greater chance of health problems [11].

About the Author

Carlos Tello

Carlos Tello

PhD (Molecular Biology)
Carlos received his PhD and MS from the Universidad de Sevilla.
Carlos spent 9 years in the laboratory investigating mineral transport in plants. He then started working as a freelancer, mainly in science writing, editing, and consulting. Carlos is passionate about learning the mechanisms behind biological processes and communicating science to both academic and non-academic audiences. He strongly believes that scientific literacy is crucial to maintain a healthy lifestyle and avoid falling for scams.


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