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Why we age: Genomic Instability

Why we age: Genomic Instability
Date Published: 08/17/2021
Date Modified: 08/19/2021

 

We take a look at genomic instability, also known as genetic instability or genome instability.

What is Genomic instability?

As described in the Hallmarks of Aging [1], genomic instability is the result of damage to our DNA that is not repaired. This is one of the nine proposed reasons we age, and it leads to genetic mutations and an increased risk of cancer.

Our cells rely on a stable genome to accurately transmit genetic material. In the case of germline cells it passes that genetic information from one generation to the next. For somatic cells this means dividing to form new cells. This process includes the error-free replication of genetic material. It also means the repair of replication mistakes and damaged DNA.

Our cells use blueprints in our DNA to produce a constant supply of proteins and other materials. These are vital to cell function and survival. A large amount of information contained in the DNA is ignored during this process. This unused information is called junk DNA, the remnants of our evolutionary past.

DNA damage can affect genes and their transcription. This results in dysfunctional cells that may jeopardize tissue and host homeostasis. This is especially important when the DNA damage affects the function of stem cells. Damage to stem cells reduces the supply of replacement cells for tissue renewal.Damaged cells that cannot repair themselves will enter apoptosis. Apoptosis is a self-destruct mechanism and marks it for removal by the immune system.

Genomic instability in aging

Now, the odd dysfunctional cell is not really a huge problem. But, as we get older, an increasing number of cells succumb to DNA damage and begin to accumulate.

Eventually, the number of these damaged cells reaches a point where they can compromise organ and tissue function. Normally, the body removes these problem cells via apoptosis. Unfortunately, as we age some cells evade apoptosis.
These rogue cells take up space in the tissue and send out harmful signals that damage the local tissue. These cells are senescent cells, and are one of the reasons we age.

Another possible outcome of damaged DNA is cells that they mutate but do not destroy themselves. Instead they continue to replicate, becoming more and more muted with each division. If a mutation damages the systems that regulate cell division or disables the tumor supression, cancer is the result.

The unchecked and rampant cell growth of cancer is probably the most well-known consequence of DNA damage.

What is the cause of genomic instability?

There are many ways for DNA to become damaged. UV rays, radiation, chemicals, and tobacco can all damage our genome. Even chemotherapy agents designed to kill cancer can also potentially damage DNA. Such toxic agents can also create senescent cells, leading to later relapse [2].

Finally, even if we avoided all the external threats to our DNA, the body still damages itself. Oxidative stress produced by our metabolism can damage both DNA and mitochondrial DNA. Double strand breaks are often the result of this metabolic damage and can be lethal to the cell.

How do cells repair DNA damage?

Thankfully, we have a network of repair systems and mechanisms that can fix most of this damage. We have enzymes that can detect and repair broken strands of DNA and reverse alterations made to base pairs.

Unfortunately, this repair process is not perfect, and, sometimes, the DNA is not repaired. This can lead to the cell replication machinery misreading the information contained in the DNA, causing a mutation.

To prevent mutations passing to daughter cells, the cellular machinery checks DNA integrity before and after replication. Unfortunately, some cells still manage to slip through the net.

How does DNA damage cause cancer?

Damaged DNA can lead to mutations which cause the cell to become cancerous and multiply without control. A possible approach to cancer may be to develop therapies that boost DNA repair. This may provide a way to prevent cancer by reducing risk factors for the disease.

Another possibility is developing therapies that repair the genome of cancer cells to make them normal cells again. There have been some initial demonstrations of this in cell studies. A therapy that could restore genome stability may prove an effective cancer treatment. This is especially so in the context of relapse.

Cancer is the most well-known disease associated with DNA damage. But, there are likely others that are linked to damage to the genome.

How does genomic instability cause progeria?

The progeric diseases are further examples. Progerias are congenital disorders that result in rapid aging-like symptoms and a dramatically shortened lifespan, with Hutchinson-Gilford progeria syndrome (HGPS) probably being the most well known. The disease is caused by a defect in Lamin A, a major component of a protein scaffold on the inner edge of the nucleus called the nuclear lamina. The lamina helps organize nuclear processes, such as RNA and DNA synthesis, and lamins are responsible for supporting key proteins in the DNA repair process.

This defect leads to HGPS sufferers only living until their early 20s and developing atherosclerosis, stiff joints, hair loss, wrinkles, and other characteristics that are similar to accelerated aging.

Conclusion

Despite the various repair systems that we have evolved, our bodies are constantly being assaulted from exposure to environmental stressors and even damaged through their own metabolic processes. Coupled with this, our repair systems also decline in effectiveness over time, meaning that DNA damage and mutations are inevitable.

There is some evidence to suggest that caloric restriction may help combat this, but as of now, no drugs or therapies are available yet that can prevent or repair DNA damage. The good news is human trials for DNA repair are launching this year at Harvard, and other researchers are also working on their own solutions. One thing is almost certain: in order to reduce cancer risk as we grow older and potentially increase healthy lifespans, rejuvenation biotechnology will need to find ways to repair our genomes.

For the time being, the best we can do is to avoid risks, such as excessive sun exposure, industrial chemicals, and smoking; of course, we also have to stay away from radioactive waste, as there are no comic book superpowers from these mutations!

Literature

[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[2] Demaria, M., O’Leary, M. N., Chang, J., Shao, L., Liu, S., Alimirah, F., … & Alston, S. (2017). Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer discovery, 7(2), 165-176.