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Quick overview of what you’ll learn from this blog post:
- What is loss of proteostasis?
- Why does proteostasis happen?
- What does loss of proteostasis cause?
The Hallmarks of Aging describes the loss of proteostasis as the failure of our protein production machinery and is one of the reasons we age.
To better understand how this affects aging, let’s break down what proteins do, and where they go wrong.
Proteins are involved in almost everything
Not everything that happens in our body is directly due to proteins, but do regulate almost everything in our body.
Proteins are the real workhorses of the cell and deal with a diverse range of tasks such as copying our DNA during replication, converting starch into sugar, and regulating the function, and structure of our tissues and organs.
Proteins contain hundreds, sometimes even thousands of smaller parts called amino acids that link together in long chains. There are a total of 20 amino acids that combine in many different ways to create a protein. These amino acids are:
- Alanine
- Arginine
- Asparagine
- Aspartic Acid
- Cysteine
- Glutamic acid
- Glutamine
- Glycine
- Histidine
- Isoleucine
- Leucine
- Lysine
- Methionine
- Phenylalanine
- Proline
- Serine
- Threonine
- Tryptophan
- Tyrosine
- Valine
- Selenocysteine
- Pyrrolysine
The proteostasis network
Our bodies rely on a flow of stable, correctly folded, and appropriate proteins in order to remain healthy. This healthy balance of protein production is known as proteostasis and is maintained by a system known as the proteostasis network, itself made mainly of proteins.
The parts of the proteostasis network are as follows:
| Ribosomes | Translates ribonucleic acid (RNA) into proteins. RNA is an important molecule in our cells that is used to construct other proteins. |
| Chaperones | Chaperones are a group of proteins that assist in protein folding by guiding the target protein to the correct form. |
| Proteasome | Protein complexes which degrade unneeded or damaged proteins marked by ubiquitin for destruction. |
| Lysosomes | Sacks of digestive enzymes within a membrane that can engulf and break down unwanted proteins and recycle them back into their base amino acids to be used to make new proteins. |
| Ubiquitin | A medium-sized polypeptide that can be attached to any protein to mark it for regulatory action. Ubiquitins can be used to mark unwanted proteins for recycling by the proteasome. |
How proteins are made
The proteostasis network starts off with a ribosome which translates a messenger RNA sequence into a protein. The sequence determines the order the amino acids in the chain, the primary structure of the protein.
As the chain forms, it naturally twists and folds to form secondary structures. The most common secondary structures that chains form are α-helixes, β-sheets and turns.
As these secondary structures form, they too interact with each other just like the amino acids on the chains do. This causes the formation of three-dimensional folds and is considered the tertiary structure.
Lastly, this tertiary structure can function alone or it can join with others to form a greater quaternary structure.
What could possibly go wrong with all this machinery?
As you may have guessed, protein creation is a complex process where a lot can go wrong.
That’s where proteostasis comes in. Normally, our proteostasis network does a great job of fishing out broken and unwanted proteins. But as we age, our body’s proteostasis network starts to deterioate, which can lead to too few proteins, too many proteins, and misfolded proteins. This is loss of proteostasis
The most common issue that aging leads to is the build up of misfolded proteins, but loss of proteostasis allows too many misfolded proteins to stick around in our body. These bent, misshapen proteins end up gathering in clumps known as aggregations. Aggregations of misfolded proteins may cause age-related diseases such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis.
But how do proteins end up misfolded?
- Environmental stress
Changes such as a rise or fall of pH or oxidation levels can cause proteins to bond with other types of proteins which, under normal conditions, they would not do. Extremes of heat or cold can also disrupt the interactions between the amino acids in chains which causes the protein structure to lose shape. - DNA mutations and translation errors
can also create misfolded proteins. Both of these things can lead to RNA that codes the incorrect amino acid. A similar situation can occur even if the RNA is correct, but the wrong amino acid gets added to the chain. If the incorrectly added amino acid is important for protein structure this can lead to the protein being structurally weak. Conditions such as cystic fibrosis are due to a mutation that makes mucus secretions thicken and build up in the lungs and digestive system. - The loss of chaperones
proteins that assist in protein folding, can also be a problem. It can happen due to a failure to transcribe DNA correctly, or due to the chaperones becoming trapped in protein aggregations. Trapped chaperones are characteristic of conditions such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. - The failure of degradation machinery
By “machinery,” we mean our body’s processes like proteasome and lysosome. When these processes fail, they can prevent misfolded proteins from breaking down and recycling. - Increasing aggregation
Once aggregations build up, other proteins that would otherwise break down become attached to the aggregation. This leads to a vicious circle where more and more proteins join the aggregated mass. The prion protein is a prime example of this and a change to its structure is the basis for Mad Cow disease, a deadly neurological disorder that destroys the brain and spinal cord over time and can jump species.
What can we do about loss of proteostasis?
Researchers are working on drugs that can potentially address the accumulation of misfolded proteins but practices such as fasting and caloric restriction may also boost autophagy which may help.
Among the options that researchers are currently exploring are drugs like Tadalafil. Though Tadalafil is normally for erectile dysfunction, its true function is as a PDE5 inhibitor, which helps relax blood vessels and improve blood flow. Scientists at Harvard recently discovered that this same mechanism of action signals a molecule known as cGMP, which increases the activity of enzymes that contribute to misfolded proteins.
Researchers are also working on ways to improve degradation systems such as autophagy boosters, as well as other drugs that may block, remove, or slow the creation of misfolded proteins.Block, remove, or slow the creation of misfolded proteins using drugs
If researchers successfully find ways to slow down the accumulation of misfolded proteins or their disposal, it could mean that diseases such as Parkinson’s and Alzheimer’s could have a solution.
Note: The above statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.