If you know about the 9 Hallmarks, you know about cellular aging.
But what do you know about structural aging?
Do you know what it is or what causes it? Or that it’s just as damaging as cellular aging?
Do you know that it’s largely been ignored by research?
If not, you’re gonna want to watch today’s video.
Cellular aging gets most of the attention, and most of the research.
After all, most of the 9 Hallmarks are just different forms of cellular aging.
But there’s another type of aging called structural aging,
and it’s structural aging that causes droopy, crepe-y skin and high blood pressure.
And as fas as I know, there’s only 1 cause: the stiffening of the extracellular matrix.
There are two types of aging. The first, cellular aging, is something that we’ve all heard of.
It’s the type of aging that is represented by the hallmarks of aging.
Genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, cellular senescence,
stem cell exhaustion…all examples of cellular aging.
But there’s another type of aging, and that’s structural aging.
Cellular aging happens within the cells.
But outside of the cells there’s a network of proteins and minerals that provides structural and biochemical support for the cells.
This network is known as the extracellular matrix, or ECM, and it too, can age.
That’s what structural aging is.
Think of it like this. Imagine people living in an apartment building.
Now, imagine that all the living things in the building are cells.
The people, their dogs and cats, their hamsters and goldfish.
The mice that live in the walls, the ants and spiders and cockroaches.
Even the mold and bacteria. They’re all cells in this analogy, living alongside one another inside of the building.
If the living organisms are the cells, then the building is the structure that supports the cells.
In biology, this structure is known as the extracellular matrix.
The ECM is like a lattice that wraps around our cells and provides a support structure.
And since the different types of tissue, like our skin tissue, our muscle tissue, our heart and liver and lung tissue,
all must be flexible and elastic, so must our extracelllular matrix be flexible and elastic.
Like the apartment building, the extracellular matrix is made up
of organic and inorganic materials, but it’s not “alive”, not like our cells are.
It’s composed of molecules, not cells.
And these molecules have a long lifespan, usually as long as the human body does, around 100 to 120 years.
There’s a very low turnover of these molecules, and as you’ll see later, this will become very important.
These molecules are primarily protein molecules, and the main structural
molecule in the extracellular matrix is collagen.
Collagen is the most abundant protein in mammals and it makes up 25% to 35% of the protein content in the body.
Alright, getting back to our analogy. All the creatures living in the apartment building age.
Each species in the building could represent a different type of cell, a different type of tissue.
And each of the different “tissues” age at a different pace. But they all age. This is cellular aging.
But the apartment building that they live in, the structure that supports and protects them, also ages.
This is structural aging.
Just as the building ages with time and becomes increasingly less functional, so does the extracellular matrix age.
And as it ages, it becomes stiffer. This is known as the stiffening of the extracellular matrix, or ECM stiffening.
And ECM stiffening has been suggested as the 10th Hallmark of Aging.
In September of 2020, two researchers, Alexander Fedintsev and Alexey Moskalev published a paper
in which they recommended that the stiffening of the extracellular matrix be considered as an additional hallmark of aging.
In fact, they went so far as to suggest that this phenomenon might be the upstream cause of several known hallmarks of aging,
such as cellular senescence.
We’re going to shift our focus for a moment and talk about a phenomenon known as glycation.
Within the extracellular matrix, the protein molecules are constantly bathed in a solution
that contains glucose molecules, which are highly reactive.
Sometimes, as a glucose molecule slides by a protein molecule, the glucose can have a reaction
that binds the glucose molecule to the protein.
Glycation is the process where molecules of glucose bind with protein molecules,
forming toxic crosslinks that can alter the physical properties of tissues and cause inflammation.
Now, inside of cells, protein molecules get turned over so fast that these bonds don’t really get a chance to build up.
But in the extracellular matrix, it’s different.
Remember when I mentioned earlier that the protein molecules in the ECM have a very slow turnover rate?
Well, it’s that slow turnover rate that allows for these bonds between glucose molecules and protein molecules to persist.
And to proliferate.
As these molecules bind to one another, over time they form long chains.
These long chains are known as crosslinks and the long molecules that create the crosslinks are known as
Advanced Glycation End-products, or AGEs.
I’ve also heard of them called Accumulated Glycation End-products.
Now, as these crosslinks are formed, particularly collagen cross linking,
as these molecules that are supposed to be unconnected and capable of freely moving about become linked together,
they form a fibrotic structure that stiffens up, causing the extracellular matrix to lose elasticity.
And it’s the gradual build-up over time of these long chains of crosslinks that causes the stiffening of the extracellular matrix,
also known as ECM stiffening.
That’s structural aging. And there’s no going back.
ECM stiffening is considered to be irreversible.
As we age and cellular repair processes fall into decline,
the repair enzymes of the cells cannot break these bonds and reverse the cross linking.
The downstream effects of ECM stiffening are profound.
Vascular stiffening, or the stiffening of our veins and arteries, is just one example of ECM stiffening.
And that example is the cause of high blood pressure, which in turn can lead to cardiovascular disease, stroke and heart attacks.
But ECM stiffening can manifest in other organs.
In fact, it can manifest throughout the body. It can lead to kidney failure and lung fibrosis.
It can lead to cognitive decline. But it’s in the skin that’s where ECM stiffening becomes most evident.
As the extracellular matrix in the skin stiffens up, the skin begins to lose elasticity.
It’s starts to droop. It becomes crepe-y looking.
It becomes wrinkled.
ECM stiffening is the cause of aging in the skin.
In fact, ECM stiffening can cause all sorts of damage.
Migrating cells, such as our immune cells, can get damaged as they try to squeeze though the narrowing gaps in the matrix.
And ECM stiffening can also ignite low-level, chronic inflammation.
And worst of all, consider this.
Since the molecules of the extracellular matrix, like collagen and elastin, last so long,
and because crosslinks can’t be repaired or reversed, the cross linking will continue to get worse and worse
until eventually, it’ll destroy these molecules.
And because they turn over so slowly and never get replaced by new molecules, once they’re destroyed and the ECM becomes too rigid,
that’s kinda it.
The resulting decrease in tissue elasticity places an upper limit on our cardiovascular and pulmonary systems
of about 100 to 120 years, the age of these molecules.
And that puts a cap on all hopes of extending the lifespan beyond the point at which these molecules fail.
If we want to extend the human lifespan, we’re going to have to find a way to break down these AGEs.
To break the bounds between the glucose molecules and the protein molecules.
And to restore flexibility and elasticity to the extracellular matrix.
Unfortunately, there hasn’t been that much recent research into structural stiffening.
Not because these crosslinks haven’t been a target of research. They have.
These targets have been recognized since the 1990’s.
Researchers have been looking for a drug that could break down these AGEs, that could sever the bonds and destroy these crosslinks,
and they’ve been looking for at least 2 or 3 decades.
But there hasn’t been much success.
For example, back in the early 2000’s there was a company called Alteon,
and they were researching a drug called Alagebrium, or ALT-711.
It was a small molecule that targeted the crosslinks caused by AGEs, but it wasn’t the only molecule.
There were other small molecules that were in development for targeting these crosslinks.
However, it turns out that the design of small molecules won’t allow for targeting them with very much specificity,
and none of these drugs proved to be successful.
Without success, interest waned, most researchers turned their focus to cellular aging, and research into structural aging
was kinda put on a back burner.
That is, until recently. In the last couple of years, interest in structural aging has picked back up.
I mentioned earlier the paper that was published by Fedintsev and Moskalev.
Other researchers have founded two biotech companies that seem to be on the brink of producing some results:
one is called Juvify and the other is Revel Pharmaceuticals.
Now, I don’t know a lot about either of these companies, but their research looks promising.
Juvify was founded by Professor Pankaj Kapahi
He’s a professor at the Buck Institute for Research on Aging.
Juvify has developed a supplement called GLYLO, for GLUcose LOwering, that can limit the production of AGE’s.
It’s created from micronutrients that have been labeled GRAS, or generally-recognized-as-safe.
These include alpha lipoid acid, nicotinamide, which is a form of vitamin B3, pyridoxamine, or vitamin B6,
thiamine, or vitamin B1, and piperine, a component of black pepper that increases bioavailability.
They claim that it can “reduce carbohydrate intake, promote fat burning, enhance NAD+,
lower amounts of AGEs, reduce senescence, and promote cellular repair pathways.”
By early next year, Kapahi hopes to publish some compelling pre-clinical data on GLYLO in mouse
studies and to start clinical trial on humans.
However, since it’s made from GRAS compounds, each of which has been proved in several clinical trials to be safe,
they’re making it available for purchase now on Amazon.
The other company that is working with AGE-breakers is Revel Pharmaceuticals, and this is really exciting.
Revel was founded last year by Dr. Aaron Cravens and Yale professors David Spiegal and Jason Crawford.
They’re taking an approach that’s different from Juvify.
They’re reviving the search for drugs that can break the crosslinks, but they’re not looking at small molecules.
They’re looking at very large molecules, and you've heard of them - they're enzymes.
Enzymes can be highly targeted with a degree of control that can’t be found in small molecules.
Dr. Craven says that “Enzymes are biologics, so we can be very precise as we make modifications
to repair damaged proteins and break up crosslinks.”
Revel started out looking at an advanced glycation end-product called glucosepane,
but they have now identified several AGEs as candidates for their enzymatic therapies.
They’re preparing to move therapeutic enzymes into pilot studies in animal models and hope to have a candidate
for Phase 1 trials by 2024.
Now, there’s probably other companies out there that are researching structural aging,
but these are the only ones that I’ve heard of.
At any rate, after decades of research that didn’t go anywhere,
it looks like we’re finally seeing some hope out there for restoring and rejuvenating the extracellular matrix
and eliminating some of the causes of structural aging.
That wraps up another video.
If you’d like to learn more about the 9 Hallmarks of Aging, you just might want to watch this playlist on, you guessed it,
the Hallmarks of Aging.
That’s it for me, I’m outta here.
Catch ya next time.