Proteins. They’re everywhere.
They compose almost all of the tissues, organs, hormones and enzymes in our body.
Every cell in every tissue is built out of protein.
But what happens when the machinery that builds and maintains healthy proteins goes haywire.
That’s loss of proteostasis, and the subject of today’s video.
Today we’re diving into Loss of Proteostasis,
which is when the machinery that maintains healthy protein creation starts to malfunction,
and it’s one of the primary Hallmarks of Aging.
Proteins are used to regulate most bodily processes, they’re used in cellular messaging,
in the functioning of all of our organs and not only the contraction of our muscles but the very structure of those muscles…
the loss of function in those proteins has wide-spread effects downstream and is one of the major sources of aging.
So today, we’re going to be examining what proteostasis is,
how the loss of proteostasis can impact the aging process, and what, if anything, can be done about it.
Let’s start this discussion with a quick look at what proteins are, how they’re formed and the functions they serve.
Proteins are large and complex molecules that are formed by linking together smaller molecules called amino acids.
There are 20 different amino acids and they can be linked together to form countless different proteins.
And these proteins serve a lot of different functions in the body.
They regulate just about everything, and when they’re not acting in some reaction,
they’re acting as a catalyst in some reaction.
They can act as antibodies, binding to specific foreign particles such as viruses and bacteria, protecting the body from infections.
They can act as enzymes to carry out almost all of the thousands of chemical reactions that can take place in cells.
They can act as messengers and hormones, transmitting chemical signals between cells, tissues and organs.
They can provide structure and support for cells.
As muscle tissue, they can move our bodies.
OK, so proteins are formed when a molecule called a ribosome grabs onto amino acids and
strings them together into a long chain,
based on a variety of templates that come from translating messenger RNA, or ribonucleic acid.
As these chains are formed, they naturally start folding into one of three different secondary structures:
α-helices, β-sheets, or turns.
Here’s a representation of the structure of a protein.
The curly parts are examples of an alpha-helix,
and the flat parts are examples of beta-sheets,
and these this parts where the chain changes direction is an example of a turn.
These chains of amino acids are known as polypeptides,
and these polypeptides can can interact with each other in the same way that amino acids can,
folding into 3D tertiary structures.
Now, these tertiary structure can function alone, or they can join with other polypeptides and fold into quaternary structures.
Now, when chains of animo acids fold, they tend to fold into structures that require the least amount of energy.
But there are proteins called chaperones that can guide polypeptides to fold into correct tertiary and quaternary structures that require more energy.
OK. So, all of this stringing together of amino acids and the folding of those chains into a variety of structures is how proteins are formed.
And how a protein is folded determines the function of that protein.
A misfolded protein doesn’t function properly.
Alright, let’s move on. Let’s talk about what proteostasis is.
The word is formed from the fusion of two words.
Proteo, which refers to the molecule that we know as a protein,
and Stasis, which means to keep the same.
So proteostasis refers to when the machinery that produces proteins is functioning as it should.
The proteins in the body are stable and healthy.
They’re folded correctly, there’s not too many or too few of specific proteins,
and the proteins are bound to anything that can cause them to malfunction.
Proteostais is maintained by a network of machinery known as the Proteostasis Network.
The proteostasis network itself is made up largely of proteins, and it has a number of different elements.
First, there’s the ribosomes.
These are the proteins that can actually produce new proteins by translating the messenger RNA.
Then there’s the chaperones, and these are the proteins that can guide the polypeptides to fold into specific structures.
But there’s also protein degradation machinery that’s part of the proteostasis network.
Occasionally, proteins get folded incorrectly, or damaged somehow,
and the degradation machinery breaks these proteins down into their component amino acids and recycles them.
This degradation machinery consists of lysosomes,
which are pockets of digestive enzymes that are surrounded by a membrane,
and by something called the ubiquitin/proteosome system.
Ubiquitin is a medium-sized peptide that attaches itself to a damaged protein by a series of enzymes,
and marks that protein for degradation.
Proteosomes are large, complex molecules that break proteins down into their component amino acids
in much the same way that lysosomes do.
Now, the components of the proteostasis network are highly conserved,
which means that they exist virtually unchanged across a wide variety of species.
And this means that they’re extremely important because a small change in structure can lead to a large change in function.
So they don’t charge much at all across species.
OK, we’ve talked about how proteins are formed, we’ve talked about what proteostasis is.
Now, let’s talk about what the loss of proteostasis is.
The loss of proteostasis, as a hallmark of aging,
is when the proteostasis network doesn’t do it’s job and proteins are no longer healthy and stable within the body.
Loss of proteostasis can cause too many of a specific protein the be formed, or too few.
It can cause proteins to become misfolded, or to be folded incorrectly.
And it can cause proteins to become bound to other molecules that cause them to malfunction,
or bound together in aggregations of proteins called amyloids.
These errors in protein production can accumulate over time,
and these accumulations represent the loss of proteostasis,
and they can have a major impact on the aging process.
There are a number of chronic diseases that are associated with loss of proteostasis.
Alzheimer’s, Parkinson’s, Huntington’s, Cystic Fibrosis, Amyotrophic Lateral Sclerosis,
and Mad Cow Disease can all be traced back to loss of proteostasis.
Now, you may have noticed that a lot of these age-related, chronic disease are neurological, and that’s no coincidence.
The protein degradation mechanism is activated by cell division, but neurons don't undergo cell division.
So, what causes loss of proteostasis?
Well, first up is environmental stresses, and by this I mean the cellular environment.
Changes in either pH or oxidation can lead to proteins carrying the wrong charge, ionically.
This is what can cause them to bind to other molecules, or to form aggregates of proteins.
Next up is mutations and translation errors.
RNA can code for the wrong amino acids, and this can be caused by either mutations in the DNA or by errors made during transcription.
Sometimes, the RNA can actually be correct, but the wrong amino acid can still be added, and this leads to the same effect.
The loss of chaperones can be another cause of the loss of proteostasis.
This can be caused by either the failure to transcribe the relevant DNA
or, more commonly, the chaperones can get stuck in protein aggregations.
This is known as chaperone sequestration.
Loss of degradation can be another factor in loss of proteostasis.
Proteins that are buried deep inside aggregations can be protected from degrading lysosomes and proteosomes.
But damaged proteins that would normally have been degraded can become attached to these aggregations
and be protected from degradation.
These are called contagious aggregations.
There’s a lot of ways that proteins can fall prey to a loss of proteostasis.
So, what can you do about it?
Well, researchers have come up with a few interventions, but most of them are in development.
Calorie restriction seems to be the most promising strategy that’s are available to most people.
It’s pretty well-known that calorie restriction can extend lifespans,
and one of the mechanisms to achieve this is through autophagy.
When fasting, autophagy breaks down proteins to be used as fuel, and the damaged proteins are the first go.
Rapamycin is another possible strategy, and it works in much the same fashion.
Rapamycin’s target protein, mTOR, induces autophagy,
but dosing at therapeutic levels can possibly be accompanied by unwanted side effects,
like diabetes and immunosuppression.
So, the hope is that new regulators that target mTOR might be found that can produce the same result without the same side effects.
Another possible intervention is chaperone or stabilizer replacement.
Injections of chaperones or kinetic stabilizers might possibly help proteins to assume the correct confirmation,
but these therapies are still in development and are experimental.
Finally, the proteostasis network is regulated by multiple molecules,
and supplementation of these molecules, known as proteostasis regulator supplementation,
could increase the cell’s ability to correctly fold or properly degrade proteins.
But these molecules and systems are involved in so many different pathways
that any intervention using these molecules would probably have major side effects.
So, the most promising idea is to create new molecules that can mimic these types of regulators under some,
but not all, of these conditions, and hopefully, not produce the same side effects.
Bottom line, the only promising intervention for most of us, that I’ve heard of,
is to simply fast and hope that autophagy can reverse the effects of loss of proteostasis.
If you’ve enjoyed this video on the loss of proteostasis,
then you’ll want to watch the rest of this playlist on the Hallmarks of Aging.
That’s it for now, I’m outta here.
Catch you guys next week.