Today, we’re taking a look at the primary Hallmark of Aging. Genomic instability.
Damage to the DNA.
It’s upstream from all the other Hallmarks, and it can impact on all aspects of aging.
Today, we’re gonna be covering Genomic Instability.
We’ll be looking at what it is, what causes it, how it impacts aging
and what the hell we can do about it.
Alright. What is Genomic Instability?
First, were gonna talk about genomic instability from a Hallmarks of Aging point-of-view.
The Hallmarks are broken into 3 categories:
the primary hallmarks, the compensatory hallmarks
and the integrative hallmarks.
The primary hallmarks are just that: the primary causes of aging.
The compensatory hallmarks are hallmarks that occur in order to compensate for the primary hallmarks.
And the integrative hallmarks are functional declines that incorporate the first two categories of hallmarks.
The upstream hallmarks impact the downstream hallmarks,
and improving the upstream hallmarks usually improves all of the downstream hallmarks.
Genomic instability is a primary hallmark. In fact, it is THE primary hallmark.
It’s the one hallmark that impacts everything downstream from it.
And it’s the most basic kind of damage that there is.
Our DNA contains the blueprint for building every type of tissue in our bodies,
for all of the processes that go on in our bodies and for all of the repairs that happen.
In order for our bodies to function perfectly, we need that blueprint to be pristine.
When it becomes damaged, tissues and processes become dysfunctional
…and we age.
Genomic instability is when the DNA becomes damaged,
when our blueprint somehow becomes faulty
and those faults get passed on when cells replicate.
And this usually happens as a break or a lesion in the strand of DNA.
Now, there’s a lot of different types of DNA damage, and they happen all the time.
A typical cell suffers between 10,000 and 1,000,000 lesions…per day.
When cells divide, or replicate, mistakes are made in the copying process
at a rate of about 120,000 times per replication.
That’s in a single cell. Over the course of a cell’s life, that’s a lot of breaks.
Now, take that and times it by the number of cells in the body
and you get a pretty good idea of the amount of mistakes that our DNA is constantly undergoing.
The cause of all these breaks can be divided into two categories.
External, or exogenous stresses and
internal, or endogenous stresses.
External stresses are things like exposure to the UV rays of the sun,
smoking cigarettes, excessive alcohol consumption, radiation, emotional stress,
certain foods, not having a high enough activity level,
and of course, diseases and the medications that you take to fight diseases.
Internal stresses come in a couple of different flavors.
First, there’s oxidation, and this seems to be the primary internal stress.
Reactive Oxygen Species, also known as ROS,
is a product of the mitochondrial respiratory chain, and to a lessor degree,
some intracellular enzymes and it seems to be the main culprit for oxidation.
But there’s another form of internal stress and that’s replicative stress.
When cells divide or replicate, the strand of DNA get split in half
and each half acts as a template for producing a completely new stand of DNA,
in a process a called DNA replication.
But sometimes, the strand get replicated incorrectly and a mutation happens.
This is replicative stress.
All of these stresses can inflict damage on the DNA
and that damage can take a lot of different forms.
It can be point mutations in the DNA, it can be either insertions or deletions in the DNA,
it can take the form of chromosomal rearrangements,
or it can be whole chromosomal numerical changes…
which permanently change the information in the content of the genome.
Now, this has been happening ever since we were single-celled organisms,
and we’ve evolved some very sophisticated defenses against these breaks in our DNA.
And these defenses take 3 forms.
The first line of defense is that the body simply tries to eliminate any and all
of the molecules that can damage our DNA before any damage actually occurs.
Failing that, the second line of defense comes into play, and this is the primary form of defense.
The body has developed very sophisticated repair processes that can identify breaks in our DNA and fix them.
These repair functions go on all the time, and this is how the body deals
with all of those constant breaks and lesions that happen to our DNA.
As fast as these breaks happen, the breaks are being repaired.
For the most part.
But sometimes, something happens.
A call goes out for a repair, but it gets ignored and the repair doesn’t happen.
Or it does happen, but it happens incorrectly.
Regardless, there’s some type of permanent damage that results.
And over time, as we age, this damage starts to accumulate.
This is genomic instability.
But the body’s not done yet. It still has a 3rd line of defense to bring to the battle.
If the body can’t repair the DNA, then it tries to eliminate the damage from the cell itself.
And it has a few different processes for accomplishing this.
First, there’s autophagy, which is a recycling process that goes on inside of the cell.
Damaged proteins are broken down into amino acids and recycled.
However, if the damage is so severe that the cell start to malfunction,
then the body attempts to eliminate the cell through apoptosis, or “programmed cell death.”
It simply kills off the offending cell and replaces it from the stock of stem cells.
But some cells avoid apoptosis and don’t die.
So the body then enforces cell cycle arrest,
which is when the cell stops replicating.
When this happens, the cells doesn’t actually die
and instead become a kind of zombie cell called a senescent cell.
But as we get older, these wonderful repair processes start to go into decline.
And the damage starts to happen faster than it can be repaired.
The damage starts to accumulate, and we start to age.
Genomic instability impacts everything downstream from it.
Damage to the DNA located at the ends of the chromosome causes telomere attrition.
It also causes the proteins to fold incorrectly, resulting in loss of proteostatsis.
It can wreak havoc with the metabolism,
causing both deregulated nutrient sensing and mitochondrial dysfunction.
Cellular senescence is a compensatory response to genomic instability.
Genomic instability causes stress in the normal cell cycle, it causes changes in
both gene expression and in gene regulation.
It also goes a long way in explaining age-related cellular degeneration
and the decay in cellular function.
And if left untreated or unrepaired,
it will eventually result in an accumulation of damaged cells
known as metastatic tumors.
The aging of humans is the ultimate outcome of genomic instability.
So, what can we do about it?
Right now, most of the medical interventions that science
has either developed or is in the process of developing,
impact the cascade of events that follow genomic instability.
There’s really not much that we can do right now
that can actually impact the lasting damage that can happen to the DNA.
When it comes to genomic instability,
most of the interventions have to do with boosting the ability of the body to
either repair the damage to the DNA or to eliminate the damaged cells.
In a paper that was published in January of this year,
researchers listed 6 areas of intervention in the DNA damage cascade.
These include DNA repair stimulators, DNA damage response targets,
metabolite interventions, metabolic responders,
autophagy inducers and senolytics.
I’ve put a link in the description to the paper and I recommend that you take a look at it.
There’s some really interesting information in it.
But here’s the thing. Longevity research is in it’s infancy.
This field is maturing rapidly,
with new discoveries and breakthroughs happening almost daily.
As it matures, it seems pretty likely that scientists will discover an intervention
that will be capable of restoring DNA to pristine conditions, and stop aging in it’s tracks.
If you enjoyed this video, then check out the rest of the videos in this playlist
on the Hallmarks of Aging. That’s it for me, I’ll catch you guys next week.