DNA Damage, Epigenetics, and Aging
Damage to our DNA is correlated with various aging processes, and recent work shows that it also changes the epigenome
DNA and aging
We may be made of star stuff, but it’s our DNA that (partially) determines what shape that star stuff will take — and how that shape will change over our lifetime.
Each of our cells contains the complete DNA recipe for a human being. The difference between cells reflects the different sequence of gene activation, but the genome — barring mutations that arise after conception — is the same in each cell. Most of the DNA of the human genome is found in the cell’s nucleus, with some small DNA fragments floating around in the mitochondria.
Certain chunks of DNA are genes, sequences that code for a protein. Those DNA sequences are transcribed into messengers RNA which is then translated into a sequence of amino acids. Linked together, these amino acids make a protein. There are also genes that influence the activity of other genes. They are called transcription factors, and… some of those appear to be quite important in the processes of aging.
This brings us to the focus of this post.
DNA is not flawless. Errors can occur during replication, can be passed on through reproduction, or can be induced via external factors. Such errors are mutations. Some of these mutations can lead to disease. But they’re not all bad. For example, a recently identified mutation appears to protect against Alzheimer’s disease.
Beyond mutations, another very annoying thing that happens as we age is that our genome becomes unstable. It’s actually one of the seven hallmarks of aging. Reactive molecules, UV exposure, pollution… All of those compound as we age and all of them can damage DNA. Our cells are exceptional DNA repairers, but too much is too much. Mutations occur, lesions appear, the whole apparatus starts to sputter. And we age.
As it goes in biology, things get even more complicated. Let’s add another level to all this by introducing epigenetics.
Epigenetics involves the study of tags that are added or removed from DNA. Epigenetic modifications can change the activity of specific genes, and gene activity is known to affect various processes involved in aging, such as the functioning of our brains. Epigenetic tags, often in the form of methyl groups, that alter gene expression can even make genetically identical worms experience differences in lifespan. Even more, optimizing that gene expression increased longevity.
Epigenetic alterations are also a suspect in how hibernation in some animals seems to slow down aging, or in how queens in eusocial species outlive workers.
Linking DNA damage and epigenetics
A new review now links DNA damage and aging in the epigenome. If we think about this for a second, it does make sense. The epigenetic tags have to be able to find their target genes and then bind to them. Changes in the DNA could potentially affect these processes.
The authors distinguish six links between DNA damage and epigenetics that may contribute to (epi)genetic aging, three of which involve the histones, the proteins around which DNA curls itself to form chromosomes.
- Histone post-translational modifications: after they’ve been put together, histones are often modified to ensure that the DNA (un)wrapping goes well. With age, these modifications can go awry.
- Histone variants: during aging, the usual histones are sometimes replaced by variants (a possible reason why is that some histone variants aid in DNA repair). But these variants — helpful in one aspect — could negatively affect the DNA wrapping process.
- Histone loss: DNA damage can ‘evict’ histones from their place and kick ’em to the curb.
These three histone-related changes often result in looser DNA packaging. This can expose genes that are not supposed to be exposed. Of course, the cell needs access to genes if and when they’re needed, but constant access opens up the DNA to a lot more possibilities to be damaged. And there are genes you don’t want to have on all the time.
The three other links between DNA damage and epigenetics are:
- Chromatin remodeling: chromatin is the combination of DNA and histones (as well as other scaffold proteins) into tightly packaged chunks of chromosomes. DNA damage can remodel this structure, also causing looser packaging.
- DNA methylation: DNA damage can remove epigenetic tags. Either they stay away, or, if the cell manages to fix the damage, they have to reattach, which can go wrong.
- ncRNAs: non-coding RNAs are not translated into protein, but can rather act as epigenetic tags or DNA regulators themselves. Since they are still coded by DNA, damage in that DNA can affect their functioning and the epigenetic/regulatory work they do.
Of course, a lot of questions remain.
It remains to be seen whether the epigenome is faithfully restored after DNA damage has been repaired or whether epigenetic alterations in, for example, DNA methylation, histone variants, histone PTMs, or histone density, persist and gradually accumulate as damage scars with advancing age… Much work is also needed to dissect the functional relevance of DNA damage-driven epigenetic changes to premature disease onset as a function of age.
In short, it’s complicated.