What Are Epigenetic Alterations? – The Hallmarks Of Ageing Series

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In this series of articles, we discuss the nine ‘common denominators’ of the ageing process – the hallmarks of ageing. What exactly they are, how they change during ageing, and how we might be able reverse them in the future? Hopefully, by the end of this series, you will have a wider understanding of what actually makes us age.

What Are Epigenetic Alterations?

From the Greek Epi, meaning ‘near’ or ‘upon’, the epigenome is the information that your cells have in addition to your DNA code. The epigenome consists of chemical compounds that do not change the DNA sequence but still affect gene activity. These chemical modifications are known as epigenetic alterations and are important in determining which genes are switched on or off. By modifying or marking the genome, epigenetic tags act as genetic controllers, playing a pivotal role in disease and in shaping our bodies. These marks can generally be passed down from a cell to its daughter cells when it divides.

Aside from the random mutations covered in previous articles, the genetic makeup is the same in the nucleus of nearly every cell in your body. Despite all using the same instructions, cell types throughout the body are amazingly diverse in their appearance and function. Cells can specialise in this manner by only expressing certain parts of their genome. It is the epigenome that ‘decides’ which regions of the DNA are turned on or off. The epigenome can also be influenced by how we live our lives: it serves as the middle-man between our genes and our environment. Signals arriving at the nucleus of the cell, originating from sources such as food or medicines, can dictate epigenetic alterations, enabling the outside world to have a layer of control over an organism’s genetic makeup.

There are three main types of epigenetic alteration:

• DNA methylation, a process that works directly on the DNA sequence. Chemical compounds called methyl groups can be added to genes in a way that turns them on or off. In either case, the addition of a new chemical group affects how a region of DNA is recognised and read by the cell’s protein-synthesising machinery.
• Histone modification. The two metres of DNA within each of our cells is tightly wound around proteins called histones to form a compact structure called chromatin. Histones can have a variety of chemical tags attached to them, which changes how tightly or loosely they pack the DNA. A loosely packed region of DNA is more accessible to be read by the protein-synthesising machinery, while the reverse is true for tightly packed DNA.
• RNA and proteins, themselves products of gene expression, can in turn regulate the activity of genes.

An introduction to epigenetic alterations by the American Aging Association

How Do Epigenetic Alterations Relate To Ageing?

The level, type and distribution of epigenetic alteration changes throughout an organism’s life, thereby changing the expression of genes in ways that deleterious to the organism. Important genes could be turned off, thereby causing cells to function poorly or die. Conversely, epigenetic changes can render a gene overactive and result in transcriptional noise, in which the production of large amounts of RNA from certain genes drowns out the signals of other more important RNA. Studies have found age-associated changes in the expression of genes involved in inflammation, mitochondrial function and lysosomal degradation (the cell’s ‘garbage disposal’ system, used to remove damaged components). Through these changes, epigenetic alterations may impair cellular function and promote age-related disease.

DNA damage can introduce changes in the epigenome. Mutations in your DNA increase as you age (see Genomic Instability). Most DNA damage is repaired, but epigenetic changes can remain at the repair site. In particular, when both strands of the DNA double helix are broken, an unprogrammed epigenetic shutting down of genes can occur, both by causing DNA methylation and by promoting chromatin restructuring. Lifestyle factors that may affect epigenetic alterations have been identified, such as diet, physical activity and stress.

How Can Epigenetic Alterations Be Measured?

As mentioned, there are multiple types of epigenetic alteration, and each of these requires its own set of measurement approaches.

DNA methylation can be measured in a number of ways, depending on the amount of DNA, and whether it is the overall level of methylation or the methylation of a specific site within the DNA that needs to be measured. Examples include chromatography, mass spectrometry and antibody-based techniques.

Antibodies can be used to target regions of DNA that have undergone histone modifications, followed by sequencing to identify the nature of those DNA regions. Other techniques such as mass spectrometry can also be used.

Transcription of specific genes can be measured and compared using RNA sequencing, in which the sequence of RNA molecules is read, or using DNA microarrays, in which RNA is first converted into DNA, which is then labelled and measured using short DNA sequences as probes.

How Might Epigenetic Alterations Be Fixed?

In the first entry in this series of articles, we touched on the difficulty of correcting the varied genetic mutations that occur during ageing (genomic instability). Epigenetic changes should in theory be easier to address, as no irreversible changes to the DNA are involved. This means that the potential exists to reverse epigenetic changes, thereby reversing aspects of the ageing process, and there is some animal evidence that this may work in practice. For example, administration of histone deacetylase inhibitors reverses some histone modifications in mice and reduces age-associated memory impairment. Sirtuins are a group of enzymes that appear to regulate lifespan in part through the regulation of gene expression, and which can be boosted using known compounds (resveratrol).

Some progress has been made in translating these findings to humans. Last year, researchers were able to revert cells from osteoarthritis patients to a more youth-like state through ‘epigenetic reprogramming’. A pilot study last year also reported that they could significantly roll back the clock on DNA methylation using a proprietary form of Calcium Alpha-Ketoglutarate. However, we currently cannot know what the effectiveness of these approaches might be in terms of actually improving human longevity.