What causes us to age as we grow older?
Why does our skin become wrinkled and start sagging?
Why do we lose muscle mass and bone tissue? Why do we become frail, weak and decrepit?
In this video, we’ll attempt to answer those questions.
Now, if you're brand new to the concept of longevity and life extension, then this series of videos is for you.
So stay tuned.
In the previous video in this series, we covered what aging is, but not why and how it happens.
That’s what we’ll tackle in this video.
And that means digging a little deeper into the loss of information theory of aging.
If you’ll recall from the last video, we discussed how the genome, our DNA,
is written in a digital code consisting of the letters A, T, C & G.
But the epigenome is more analog, and as such,
is vulnerable to the types of data loss that all analog info is susceptible to.
So noise builds up in the epigenome and that noise interferes with data passes from the genome.
Also, in the last video, I introduced the Nine Hallmarks of Aging,
but we didn’t really get into them very much at all.
So we’re gonna do that now.
First off, the Hallmarks of Aging are divided into 3 categories:
the primary hallmarks, the antagonistic or compensatory hallmarks,
and the integrative hallmarks.
Each category tends to be caused by effects of the previous category.
The primary hallmarks are just that, the primary causes of aging.
The antagonistic hallmarks are a compensatory response to cellular damage caused by the primary hallmarks,
but if the condition is persistent, an antagonistic response can become harmful.
The integrative hallmarks are considered to be the end result of the two previous hallmarks
and are responsible for the attributes of aging and the progressive decline in function.
The first hallmark is genomic instability, and this is caused by breaks or errors in our DNA.
Although a lot of this type of damage is automatically mended by repair processes,
it’s proving difficult to fix using interventions.
Next is telomere attrition.
The chromatin fiber that makes up our chromosomes is a single strand,
and both ends are composed of non-coding, repeating sequences of the DNA
and it’s there to protect that rest of the DNA from damage…
kind of like the aglets of shoelaces, those little pieces of plastic that keep the shoelaces from becoming unraveled.
These strands of chromatin fiber at the ends of the chromosomes are the telomeres.
Every time a cell divides, the telomeres of the chromosomes get a little shorter, until they’re all gone.
When this happens, the cell stops dividing and usually dies.
This erosion of the telomere is telomere attrition, and it’s a primary cause of aging.
The third hallmark is epigenetic instability
and it’s all the changes that happen to the epigenome that aren’t supposed to happen.
This can include transcription errors, which is the simplest, the shortest-termed and the easiest to repair,
and errors in silencing proteins known as “silent information regulators”…but more on that later.
But far and away, the most common and long-lasting types of errors is methylation;
the bonding of methyl groups to the DNA.
The last of the primary hallmarks is called loss of proteostasis.
Tissue cells reproduce by splitting in half.
During this process, called mitosis, proteins, which are folded in complex patterns,
unfold so that they can be read and duplicated by RNA.
After mitosis is finished, they re-fold themselves back to their original configuration.
But sometimes they don’t.
Sometimes they re-fold in a way that is different from the way they’re supposed to be folded,
and so they don’t function properly.
This is call loss of proteostasis.
The first hallmark in the antagonistic category of hallmarks is called deregulated nutrient sensing.
There are 4 pathways in the human body that can sense how many nutrients are available in the bloodstream,
and can trigger a variety of responses.
These pathways control more different processes than I can go into here,
and when these nutrient sensing pathways get out of balance or become deregulated,
they can wreak havoc on the body.
The next hallmark is mitochondrial dysfunction.
The mitochondria are tiny organelles in cells and their primary function is to create ATP,
that universal energy source for every cell and every function in our body.
When they lose the ability to effectively produce ATP, or when they start to become scarce…
that’s mitochondrial dysfunction.
The last antagonistic hallmark is called cellular senescence.
Remember earlier when I was talking about telomere attrition
and I mentioned that once the telomere have completely eroded away the cell stops dividing and most of them die?
Well, some of them don’t die.
Instead, they become a sort of “zombie” cells that’s supposed to be dead, but isn’t.
This is cellular senescence, and they stop functioning as normal cells.
Instead, they start pumping out SASPs,
or senescent-associated secretory phenotypes
that can encourage neighboring cells to also become senescent.
The first hallmark in the integrative category of hallmark is called stem cell exhaustion.
When cells die off, they are replaced by new cells that grow from undifferentiated cells,
which are cells that aren’t really any type of tissue cell, but can become any type.
These undifferentiated cells are called stem cells,
and when the supply of these runs low, replacing dying cells becomes much more difficult.
This is called stem cell exhaustion.
The final hallmark is called altered intercellular communications.
Cells communicate with one another through chemical signaling.
This signaling is what triggers almost all of the processes that happen in the body.
When these signaling molecules are altered, it can radically interfere with these processes.
Now, we’ve only known about these hallmarks since 2013
when they were first published in a paper by Carlos Lopez-Otin.
And they describe most of the known causes of aging.
But are they really the causes of aging, or merely the symptoms of an underlying cause?
Ever since that paper was published,
scientists have been looking for a single, unified theory that describes a universal source for aging.
A single agent that can cause all of the hallmark of aging.
A researcher named David Sinclair thinks he’s found one. And I think he may be right.
Or at least, that’s what I think in lieu of another, better theory.
In the previous video in this series, I explained how, although the DNA is written in a digital code,
the epigenome is analog, and how noise can be introduced into the code.
This noise interferes with the transcription of that code, resulting in faulty instructions.
Here’s an example of how that works.
Our bodies have been evolving along a straight, unbroken line ever since the only form of life on earth were single-celled organisms.
And early on, back when we were single-celled,
we developed a nutrient-sensing pathway called SIRT,
which stands for silent information receiver/transmitter.
These are genes that code for proteins that have a dual function.
Now, originally, this was a survival function, and these genes have been called survival genes.
When times were plentiful, they allowed the organism to reproduce,
but when times were tough, they stopped reproduction and turned to repair.
For this example, we’re going to look at a protein called sir2,
which stands for silent information regulator 2 and is produced by one of these genes.
By the way, this sir2 protein, or sirtu protein,
was the first of these proteins to be discovered, in yeast,
and it’s why all of these proteins became known as sirtuins.
Sir2 has two functions, like all the other sirtuins.
One function is as a silencing protein.
In this case, it silences a gene that prevents reproduction, thus allowing the cell to reproduce.
But it’s other function is to repair broken strands of DNA.
It can do one or the other.
When it leaves the gene that controls reproduction to repair the broken DNA,
it’s no longer silencing that gene, and so reproduction stops…
because that’s what that gene does.
Now, if you think about it, this makes sense.
If you’ve got a cell with a broken strand of DNA, you don’t want that cell reproducing,
because some of the of the code will be lost, resulting in transcription errors.
Once the DNA has been repaired, the sir2 protein returns to the gene, silences it, and reproduction resumes.
All is well and good, everything is working just like it’s supposed to.
But since this event happens billions, if not trillions of times a day in our bodies,
it’s not to be unexpected that this process doesn’t always happen as it’s supposed to.
Occasionally, the sir2 proteins forgets where it’s supposed to return to after it repairs the broken DNA.
This is the type of noise that can happen to the epigenome.
In the case of the sir2, what usually happens is that both the mating genes, male and female,
to turn on at the same time, the cell forgets what it’s supposed to be and becomes sterile…
and doesn’t reproduce anymore.
This is just one example of how noise gets introduced into the epigenome.
As we have evolved, our sirtiuns have evolved and we now have 7 sirtuin genes.
And the sirtuins, along with all of the nutrient-sensing pathways,
are just one way that the epigenome become noisy…there’s a lot of other ways.
For example, methylation of the DNA.
A methyl group is a molecule that’s composed of a single carbon atom and 3 hydrogen atoms.
These methyl groups can attach themselves to the nitrogen bases of the DNA,
to the adenine, thymine, guanine and cytosine.
When you’ve got a gene with methyl groups attached to the nucleotides,
it impacts how the gene expresses. It can turn genes on or off.
Now, methylation is a normal part of the epigenome,
and it’s part of the process of how genes are expressed.
But methylation can also be abnormal, and when this happens, the genes malfunction.
As we age, more and more abnormal methylation accumulates.
This process is so predictable, that if we examine the methylation,
we can usually determine the biological age pretty accurately.
In fact, that’s how a series of biological clocks work, with the most accurate being the Horvath Clock.
Alright, that how the Information Theory of Aging works.
But let’s take a look at how it plays out in the Hallmarks of Aging
to see if this loss of information theory hold up across all aspects of aging.
If it’s a valid theory, then is should hold up.
If even a single case arises where it doesn’t hold up, then it isn’t a valid, unifying theory.
First, genomic instability.
Now this absolutely holds up because the whole idea is that the instructions in the DNA have somehow become corrupted.
Same with epigenetic alterations.
Both of those hallmarks are based on the loss of information.
What about telomere attrition.
As the telomeres erode until none is left and the actual coding information of the DNA starts to erode,
the cell interprets this as a break in the DNA.
But unlike a true break in the DNA, where there’s two ends of the strand that need to be rejoined,
here there’s only a single end.
The repair protein attaches to the strand, but it can’t find the other end to rejoin.
And so the protein is now permanently attached, since it only releases once the repair has been accomplished.
Which means that it never returns to it’s original position,
and the cell starts to malfunction, usually either dying or becoming senescent.
So this also holds up.
Loss of proteostasis?
Remember that proteins get their instructions on how to fold correctly from the epigenome.
If they’re folding incorrectly, it’s because they’re not receiving correct instructions.
Holds up.
Now, since deregulated nutrient sensing, mitochondria dysfunction
and cellular senescence are responses to the four primary hallmarks
and are made to compensate for damage done by those hallmarks,
I think it’s safe to say that they are ultimately caused by whatever cause the first four hallmarks,
which is a loss of information.
Ditto for the integrative hallmarks, since they’re the end result of the two previous hallmarks.
Not convinced?
The antagonistic and the integrative hallmarks are downstream from the primary hallmarks,
and it’s been demonstrated that cleaning up the first four hallmarks
can automatically improve the other five hallmarks.
Now, here’s the thing.
While more and more noise accumulates on the epigenome,
interfering with the proper transmission of information and instructions,
the digital code of the DNA that underlies the epigenome is still intact.
In the last video, I made the analogy of an audio CD, with the original music still being fully intact,
but the scratches on the surface interfering with the reading of the CD.
But that CD can be polished to remove those scratches,
revealing the digital code underneath and allowing that code to be read correctly.
Some thing with the DNA and our epigenome.
And the epigenome is very susceptible to change.
That’s what caused the problem in the first place.
But it’s also how this problem can be solved.
Studies have demonstrated that the alterations to the epigenome can be reversed,
and returned to a state that allows the DNA code to be read correctly.
OK, so we’ve talked about what aging is,
we’ve demonstrated that aging ultimately caused by
a loss of information being transmitted incorrectly across the epigenome,
we’ve taken a look at how this plays out across the 9 hallmarks of aging.
The only question left is: What, if anything, can be done about it?
Is aging inevitable,
or are there interventions available that can slow, stop or even reverse the aging process?
That’s what we’re going to be taking a look at in the next video in this series.
If you enjoyed this video and would like to watch the rest of the videos in this series, then check out this play list.
That’s it for me, I’ll catch ya next time.