Posted on 20 May 2021
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.
A genome is the entire set of DNA in a cell. The DNA is the cell’s instruction manual, containing all of the information needed to synthesize the proteins essential for life. Each time a cell divides it makes a near perfect copy of its genetic information to pass onto its daughter cells. Thus, the genetic code is faithfully reprinted and passed down through cellular generations.
Genomic instability refers to a high frequency of mutations within the genetic code. Likening the genome to a cell’s instruction manual, genome instability refers to the number of errors in this manuscript. These could be introduced when the text is being copied (cell division) or when somebody scribbles in the pages (when the DNA is damaged). If the mistakes in the text accumulate, soon some instructions might no longer be legible, which will impair the cell’s ability to function properly.
With ageing, the amount of damage present in the genome accumulates. Tissues composed of cells that divide infrequently or not at all, such as non-dividing nerve cells in the brain, have the time to accrue physical damage. Cells that divide more frequently also incur genetic mutations during the replication of their DNA, which is inherently error-prone. When we’re young, this damage is either repaired or is at such a low level that it inflicts no harm on our bodies. However, as the years add up, some of this damage will escape the cell’s repair machinery and will accumulate. This damage can affect the cell’s repair machinery itself, which exacerbates the problem. When the damage goes beyond a certain threshold, the cell will normally ‘commit suicide’ in a process called apoptosis, or become senescent and subsequently be removed by the immune system (senescence will be covered in a subsequent article). During ageing, as more and more cells accumulate damage and undergo apoptosis or senescence, certain organs like muscle and the brain see their function impaired.
Meanwhile, in other tissues, apoptosis fails to occur when it should. This is a problem because cells with a high level of genomic instability are more prone to becoming cancerous. Mutations in the genome alter how it is read and thus what proteins are made, but a single mutation is not usually enough to make a cell cancerous, as cells possess ‘failsafes’ that have evolved to prevent uncontrolled division. The more mutations a cell has accumulated, the more likely it is that these protections will have been damaged, to the point where just one more mutation will make the cell cancerous.
It’s worth noting that as we age, sources of DNA damage that drive genomic instability increase due to other age related changes such as mitochondrial dysfunction. It’s also worth pointing out that genomic instability occurs in the mitochondrial DNA, and this may be an extremely important driver of the ageing process. This is one example of how different hallmarks of ageing are interlinked, and will be covered in more detail when we explore mitochondrial dysfunction.
There are multiple levels at which genomic instability can be measured. At the largest scale, we can detect chromosomal abnormalities. This is when entire chromosomes are added or missing, or when the structure of a chromosome is significantly altered (such as having a large region deleted, duplicated, or swapped with another chromosome). Such changes can be measured using fluorescent DNA probes that target specific DNA sequences. This can be used to ‘paint’ each chromosome pair using a different colour and observe whether chromosomes have been rearranged. These chromosomal abnormalities happen quite frequently during ageing – for example, up to 15–20% of aged human oocytes have chromosomal abnormalities, mainly the loss or gain of a whole chromosomes.
Measuring smaller mutations, such as those that change just a single letter of the genetic code, is more challenging since such alterations cannot be observed under a microscope. Genome sequencing technology can be used to read most of the individual letters in a cell’s genetic code, allowing the frequency of mutations in a representative sample of cells to be measured. This approach does have some inherent inaccuracy, as sequencing errors are indistinguishable from genetic mutations. However, this has become less of a problem as genome sequencing technology has improved.
Genomic instability itself is not an easy problem to address directly, as it is a random process that results in a diverse range of different mutations across different cells and tissues. Technologies such as CRISPR, which is able to correct a specific genetic mutation that is known about, are therefore not able to fix genomic instability, as we would need to sequence every cell in the body and then somehow deliver tailored gene editing technology to each one of them.
We might still be able to slow the development genomic instability by tackling its underlying causes: age-related failure of genetic proofreading and repair mechanisms, and increased exposure to damaging agents. This may have the effect of slowing down the ageing process, but such a hypothesis has yet to be proven. Fixing other hallmarks of ageing is likely to address some of the drivers of genomic instability. Furthermore, scientists are studying pharmacological approaches to boosting DNA repair.
The Hallmarks of Aging: https://dx.doi.org/10.1016%2Fj.cell.2013.05.039
Effect of maternal age on the frequency of cytogenetic abnormalities in human oocytes: https://doi.org/10.1159/000086891
Pharmacological boost of DNA damage response and repair by enhanced biogenesis of DNA damage response RNAs: https://doi.org/10.1038/s41598-019-42892-6
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