Hallmarks of Aging: Genomic Instability

Hallmarks of Aging: Genomic Instability

Quick overview of what you’ll learn from this blog post:

  • What is genomic instability?
  • What causes genomic instability?
  • What are the consequences of genomic instability?

The Hallmarks of Aging describes genomic instability as being the result of damage to our DNA that is imperfectly repaired or even not repaired at all. So, what exactly does that mean?

Let’s explore.

Your DNA is gradually falling apart

Genomic instability is thought to be one of the primary reasons we age and relates to our DNA and damage to its structure. Unfortunately, over time our DNA slowly gets damaged and begins to break down with potentially disastrous consequences. This damage leads to mutations in the genome which increases the risk of cancer and alters protein production.

Our cells use our DNA like blueprints to produce a constant supply of proteins; these are critical for cellular function and survival. Damaged or mutated DNA is an important part of the genome that can lead to the cell producing misshapen proteins or stop working.

Misshapen proteins range from being useless and mostly harmless, to directly harmful. For example, Alzheimer’s disease is associated with neurotoxic misfolded proteins that harm brain cells.

Of course, a few damaged and dysfunctional cells floating around is not a huge problem. However, as we age, more of these cells accumulate and the health of the tissue or organ they are a part of is compromised.

Normally these damaged cells destroy themselves through a form of self-destruct sequence known as apoptosis and the immune system disposes of them. Some evade apoptosis and become senescent cells, no longer able to replicate but instead secreting inflammatory signals and taking up the space of healthy cells.

Then there are the more dangerous cells that evade apoptosis and do not become senescent either. Instead, they remain alive and continue to replicate with their damaged DNA which increases the risk of them developing mutations with each division.

If a mutation improves the survival chances of the cell or turns off a cell’s anti-tumor formation mechanisms, the eventual result can be cancer. Cells that divide more often are the ones at highest risk of becoming cancerous.

How does genomic instability happen?

  • UV rays
  • Radiation
  • Polycyclic aromatic hydrocarbons
  • Chemotherapy chemicals
  • Metabolic operation

UV rays in sunlight can damage our DNA and increase the production of inflammatory free radicals which can damage our mitochondria.

Radiation exposure from X-rays and gamma rays can even cause our DNA strands to break.

Polycyclic aromatic hydrocarbons can bind to our DNA and prevent it from working properly. These are a class of chemicals that are found naturally in coal, crude oil, and gasoline. They also are present in the fumes produced from burning coal, oil, gas, wood, trash, and tobacco.

Chemotherapy chemicals that are used to treat cancer can also cause DNA damage to healthy nearby cells too. Because the agents are highly cell toxic to both cancerous and normal cells the side effects can be severe and highly unpleasant.

Metabolic operation can also damage our DNA. This is because during its normal operation, your body damages itself as the result of normal metabolic operation. For example, our mitochondria produce free radicals as a byproduct of energy production which can damage our mitochondrial DNA.

The bottom line is that even if you could surround yourself with a force field and avoid all environmental sources of DNA damage, it would still happen thanks to our body damaging itself.

Repairing DNA damage

In order to remain healthy our cells depend on having a stable genome to safely pass on genetic material. For our regular somatic cells this means passing that information to new cells during division. For our germline cells it means passing that information to our children. To work successfully this genetic information needs to be free from errors and any replication errors or damaged DNA must be repaired before passing it on.

Fortunately, our cells have a variety of repair mechanisms that help to combat DNA damage. We have enzymes that can detect and reverse modifications of base pairs or even rejoin broken DNA strands.

However, this repair system is not perfect and mistakes and imperfect repairs do sometimes happen. This can mean some DNA damage remains unrepaired. Our replication machinery can then misread the damaged DNA strand, insert the wrong base into a newly created strand, and hey presto, you get a mutation!

Any mutations created could then be passed down to every daughter cell, so avoiding these errors is a top priority for our cells. This is why there are checks made on our DNA integrity both before and after replication.

There are a number of age-related diseases linked to improper DNA repair including Alzheimer’s, Parkinson’s, and Amyotrophic lateral sclerosis. Cancer is also linked to imperfect repair and while younger people do sometimes get cancer, it is predominantly a disease of old age.

What can we do about genomic instability?

Researchers are testing a number of approaches which might help to combat genomic instability.

  • NAD+ boosters to help improve DNA repair
  • Immunotherapies to more effectively destroy cancer if it does appear
  • Adding copies of mitochondrial genes to the nucleus to protect from free radicals
  • Replacing damaged mitochondria

Many researchers believe that DNA damage is a primary reason we age. Certainly, the evidence is good to support that it plays a key role in aging as well as cancer. Therapies that can protect our DNA or improve how we repair it could have a significant impact on how we age and our ability to combat cancer and other diseases.