All cells use a variety of different quality control mechanisms to ensure the functionality and stability of their respective protein diversity. Experts refer to this process as proteostasis. Proteostasis is made up of the two terms proteome (the totality of proteins that a cell can produce) and homeostasis (balance). In the optimal case, the proteins in a single cell are always folded correctly and always present in the right amount. Despite all noble efforts, our body does not manage to guarantee this optimum. In this article we will show you what aging and some age-related diseases have to do with a loss of proteostasis .
From DNA to chain to protein
First we need to get a better understanding of the molecular structure of proteins. Each protein is made in a similar way. The first step, also known as transcription, takes place in the cell nucleus and means reading and copying the blueprint from the DNA – ours genetic material.
This transcribed information is then transported out of the cell nucleus, as is a translation (Translation). This means that DNA language is translated into protein language , i.e. the protein is assembled based on the DNA blueprint. First and foremost, a protein is a long linear chain of amino acids, similar to a string of pearls. This loose sequence of amino acids is called the primary structure.
So that the proteins in primary structure can now begin their work, they still have to be folded, which is a very complex process. First, for example, the protein chain can be twisted, creating a spiral, which is called an alpha helix because of its typical shape. This form is the most common secondary structure. Through further folding steps, the proteins achieve a three-dimensional shape – the tertiary structure. In this state they combine and work with other proteins.
Did you know? The first amino acid to be discovered was cystine in 1810. It took until 1953 for an entire protein to be decoded into its amino acid sequence (primary structure). Frederick Sanger was able to decipher the amino acid sequence of insulin .
Chaperones – our body’s chaperones
You can see from the diagram that the amino acid sequence as the primary structure is not enough. In order for the proteins in our body to do their jobs, they need a few intermediate steps. It is only in the tertiary structure that the amino acids form a three-dimensional structure that is functional. It takes a lot of work to get there.
new connections have to be made and sulfur-containing bridges are formed between individual amino acids. The whole thing becomes very complex and extremely error-prone. One wrong bond and the protein is non-functional. That's why there are several quality controls in our body that are supposed to guarantee that everything is correct.
One of these quality controls are the Chaperones. If someone is interested in England and the language, the meaning is often already clear. A little tip: it is often used in the successful Netflix series “Bridgerton”.
A chaperone is therefore an older woman who accompanies a younger woman as a protector. A chaperone from England is something like a modesty protein in the body. On the one hand, it helps new proteins to fold or broken proteins to fold properly again.
Did you know? How many proteins are there in the world? The complexity of protein architecture is difficult to grasp. For this reason, scientists have developed an artificial intelligence that can predict the three-dimensional shape of a protein with high probability. “AlphaFold” was able to predict 215 million proteins and their tertiary structure in 2022 alone. The work of the researchers from Bael is considered one of the most important in recent years, because with the help of artificial intelligence, drugs and vaccines can be developed more quickly in the future.
Loss of proteostasis – how do misfolded proteins occur?
Between 40 and 80% of all proteins are folded incorrectly and need help. That is an enormous number. There are some factors that can negatively affect protein structure. These include Ultraviolet radiation, heavy metals, heat or ethanol. Especially when it comes to food or food supplements it is therefore important to pay attention to appropriate certificates.
These environmental influences influence our proteins as well as our DNA. In addition, oxidative stress - commonly known as an excess of free radicals - affects the protein balance. As if that wasn't enough, there's also the ER stress.
ER stands for endoplasmic reticulum, a facility in each of our cells whose function could be described as a logistics center. This logistics center can be overloaded due to high demand and goods can no longer be delivered correctly. What’s on Amazon, Alibaba and co. would cause a lot of trouble, is also dangerous for the cell. All of the influences mentioned can develop proteins and thus render them useless.
Proteostasis – how the body defends itself
Proteostasis includes several mechanisms in an attempt to maintain balance. For the sake of clarity, we focus our attention on two of the most significant mechanisms. In response to harmful environmental influences, the cell produces increased amounts of proteins from the heat shock family. These are very resilient proteins that can stabilize other proteins in situations of cellular stress. They do this in interaction with chaperones.
If stabilization or restoration of the correct folding is not successful, the proteins are initially unusable and must be disposed of. What the waste incineration plant or the recycling center does for us is done in the body by the proteasome. Together with a small protein called Ubiquitin (Ub), the broken molecule is marked multiple times, broken down and broken down into the individual amino acids.
All of these systems work in a coordinated manner to restore or dispose of misfolded proteins. This allows the body to prevent the accumulation of damaged components and ensure the continuous renewal of intracellular proteins. Another component of our cell-internal waste disposal is autophagy, which we describe to you as 12. Introduce Hallmark of Aging in more detail.
So much for the theory. Unfortunately, in practice there is no guarantee that these sophisticated mechanisms will work at all times. The keyword time brings us to the next point.
Did you know? There are different heat shock proteins in our body. They are classified according to their weight. As their name suggests, they are activated by heat, among other things. One of the best ways to do this is infrared cabins or sauna sessions. Increasing the concentration of heat shock proteins is associated with a number of health benefits.
In a study, the researchers were able to show that higher levels of Hsp70 could reduce the inflammatory mediator interleukin-10. This explains the researchers why sauna can help with inflammation such as arthritis.
Wrinkles – top with proteins, flop in old age
While in our imagination wrinkles are a sign of age and therefore have a rather negative impact, with proteins, as we now know, the situation is exactly the opposite.
Many studies have shown that proteostasis changes with increasing age. The chronic accumulation of misfolded or unfolded proteins contributes to the development of some age-related diseases such as Alzheimer's disease, Parkinson's disease and cataracts. The frequency of these pathologies is constantly increasing due to increasing life expectancy.
The production of chaperones in response to stress is also markedly reduced with age. Studies on animal models support the hypothesis that chaperone loss is the cause of a reduced lifespan. Genetically modified worms and flies, for example, which produce increased levels of chaperones, are particularly long-lived. Upregulation of some heat shock proteins was also found in long-lived mouse strains.
In addition, studies on mammalian cells show that upregulation of SIRT1 improves the heat shock response. SIRT1 belongs to the gene family of sirtuins, which is referred to as longevity pathways due to the numerous effects associated with aging become. Many other experiments and studies provided scientific evidence for the connection between chaperone levels and lifespan - but to name them all is beyond the scope of this article.
Proteostop
Medical-biological research has already done a lot of educational work regarding proteostasis, but are there already solid starting points for stopping the age-related weakening of proteostasis? In fact, there are many studies on this.
One approach aims to activate chaperone-mediated protein stability and folding. In a mouse model, drug induction of a specific heat shock protein preserved muscle function and slowed the progression of certain muscle diseases. In other model organisms, researchers also used chaperones and thereby improved age-related phenotypes. The chaperones of our bodies are not only gentlewomen, but also fighters on the front line against old age.
Another starting point is the proteasome and other mechanisms that serve to break down broken proteins, because studies show that the activity of these systems decreases with increasing age. This was achieved with selected enzymes that developed their effect within this complex signaling pathway.
A dietary supplement with spermidine , for example, activated the autophagy system. This means the breakdown of damaged cell structures (such as proteins). To put it simply, autophagy is similar in function to the proteasome we are familiar with.
Wrinkles – top with proteins, flop in old age
While in our imagination wrinkles are a sign of age and therefore have a rather negative impact, with proteins, as we now know, the situation is exactly the opposite.
Many studies have shown that proteostasis changes with increasing age. The chronic accumulation of misfolded or unfolded proteins contributes to the development of some age-related diseases such as Alzheimer's disease, Parkinson's disease and cataracts. The frequency of these pathologies is constantly increasing due to increasing life expectancy.
The production of chaperones in response to stress is also markedly reduced with age. Studies on animal models support the hypothesis that chaperone loss is the cause of a reduced lifespan. Genetically modified worms and flies, for example, which produce increased levels of chaperones, are particularly long-lived. Upregulation of some heat shock proteins was also found in long-lived mouse strains.
In addition, studies on mammalian cells show that upregulation of SIRT1 improves the heat shock response. SIRT1 belongs to the gene family of sirtuins, which is referred to as longevity pathways due to the numerous effects associated with aging become. Many other experiments and studies provided scientific evidence for the connection between chaperone levels and lifespan - but to name them all is beyond the scope of this article.
Proteostop
Medical-biological research has already done a lot of educational work regarding proteostasis, but are there already solid starting points for stopping the age-related weakening of proteostasis? In fact, there are many studies on this.
One approach aims to activate chaperone-mediated protein stability and folding. In a mouse model, drug induction of a specific heat shock protein preserved muscle function and slowed the progression of certain muscle diseases. In other model organisms, researchers also used chaperones and thereby improved age-related phenotypes. The chaperones of our bodies are not only gentlewomen, but also fighters on the front line against old age.
Another starting point is the proteasome and other mechanisms that serve to break down broken proteins, because studies show that the activity of these systems decreases with increasing age. This was achieved with selected enzymes that developed their effect within this complex signaling pathway.
A dietary supplement with spermidine , for example, activated the autophagy system. This means the breakdown of damaged cell structures (such as proteins). To put it simply, autophagy is similar in function to the proteasome we are familiar with.
