Why Do We Age? | Epigenetic Alterations

The 1990’s brought excitement to the concept of the human genome. Since then, scientists have come to learn that perhaps more important than the genome is the epigenome — that is, the system that regulates the expression of our genes.

When the Pianist Gets Tired and Confused

The epigenome is the complex machinery that determines how active each of our genes are. 

You can look at the epigenome as an on-off switch for genes.

Another way to picture the epigenome is to liken it to a piano player, while the genome is the piano keys. Each piano key is a gene, and the epigenome determines which keys are pressed, and how hard they are pressed. Just like one piano can play an almost infinite amount of tunes, the genome can be expressed in an almost infinite amount of variations by the epigenome. 

The epigenome is very important for gene expression (which genes are active or inactive), and thus cellular function as a whole. 

After all, all the cells in our body contain the same DNA, yet our body contains hundreds of different types of cells, such as muscle cells, neurons, liver cells, and so on. Muscle cells and liver cells have the same DNA, but look and behave completely differently, and have very different lifespans. That’s because of the epigenome. 

It’s the epigenome that determines a cell is a muscle cell, a neuron, or a liver cell. The epigenome ensures that only muscle genes are switched on in muscle cells, and that only liver genes are switched on in liver cells, and so on. The epigenome determines the identity and function of all our cells. 

The epigenome organizes itself in three main ways:

1. DNA Methylation

Methyl groups (CH3) are put on the DNA. This suppresses DNA expression: the methyl groups prevent proteins from attaching to the DNA strand so they cannot convert the DNA code into mRNA that contains the instructions to build proteins.

2. Histones

These are bundles of proteins around which DNA strands are wrapped. You can compare it to a thread of wool wrapped around a spool. The wool thread is the DNA, the spool is the histone-complex. In this way, the DNA in each cell, which is in total 1.5 meters long, can be tightly rolled up so that it fits into a cell nucleus which is only a few microns in diameter, which is an amazing feat. In fact, if you would unravel the 1.5 meter long DNA strands in all your cells and place every DNA strand one after the other, you would have a DNA chain that is twice as long as the diameter of our solar system (which is 10 billion miles). This huge amount of DNA can be wrapped up in just one human body thanks to the epigenome. 

3. Chromatin

The methylation of the DNA, the histone configuration, and many other interactions determine how the DNA organizes itself on a large scale in the cell nucleus. The chromatin enables some regions of the DNA to be closer to each other than others, which improves for example gene transcription for genes that have similar functions. This global organization of the DNA in the cell nucleus is called the chromatin.

The Aging Process

The problem is that during aging the epigenome becomes increasingly dysregulated.

Liver-specific genes are switched on in brain cells, stomach genes are switched on in muscle cells, and so on.

Genes that need to be turned off are turned on (like cancer-promoting genes), and genes that need to be turned on are switched off, such as genes that repair or protect our cells. 

Generally, we see that our DNA becomes more demethylated (there are less methyl groups sticking on the DNA which would normally prevent the DNA to be translated into protein). As a result, gene transcription is less suppressed in many areas.

This leads to specific genes becoming active that should not be active, like cancer promoting genes.

The reduction in methylated DNA also enables retrotransposons to become more active. Retrotransposons are pieces of DNA that resemble viruses: they can jump out of the DNA, copy themselves, and nestle themselves back into the DNA in random places. This disrupts the DNA, certainly when a retrotransposon nestles itself into a gene, disrupting the gene. 

During aging, we also see that certain promoter regions in the DNA become hypermethylated. Promoters are regions in the DNA that enable genes to be expressed. Hypermethylation means that a lot of methyl groups are placed on the promoter DNA. As a result, the promoters are suppressed, which in turn suppresses gene expression. 

With age, the structure and organization of the histones also becomes disturbed, so that some genes become active that should not become active, and vice versa.

NOVOS’ Approach to Epigenetic Aging