All cells utilize a variety of different quality control mechanisms to ensure the functionality and stability of their respective protein diversity. In the scientific community, this process is referred to as proteostasis. Proteostasis is composed of the two terms proteome (the totality of proteins that a cell can produce) and homeostasis (balance). Ideally, the proteins of a single cell are always correctly folded and present in the appropriate amounts. Despite all noble efforts, our body fails to ensure this optimum. In this article, we will show you what aging and some age-associated diseases have to do with a loss of proteostasis .
From DNA through the chain to the protein
First, we need to gain a better understanding of the molecular structure of proteins. Each protein is produced in a similar way. The first step, also known as transcription , takes place in the cell nucleus and refers to the reading and copying of the blueprint from the DNA – our genetic material.
Then, there is a transport of this copied information out of the cell nucleus, as well as a translation (translation). This means that DNA language is translated into protein language , meaning the protein is assembled based on the DNA blueprint. Primarily, a protein is then a long linear chain of amino acids, similar to a string of pearls. This loose sequence of amino acids is called primary structure.
In order for the proteins to primary structure to take on their function, they must still be folded , which is a very complex process. First, the protein chain can be twisted, for example, creating a spiral that is referred to as alpha-helixsecondary structure. Through further folding steps, the proteins achieve a three-dimensional shape – the tertiary structure. In this state, they connect and work with other proteins.
Did you know? The first amino acid to be discovered was cystine in 1810.Until a whole protein was deciphered in its amino acid sequence (primary structure), it took until 1953. Frederic Sanger was able to decipher the amino acid sequence of insulin .
Chaperone – The ladies-in-waiting of our body
You can see from the diagram that it is not enough to have the amino acid sequence as the primary structure. For the proteins in our body to perform their tasks, they require some intermediate steps. Only in the tertiary structure do the amino acids form a three-dimensional structure that is functional. To get there, a lot of work is necessary.
New connections must be formed and sulfur bridges are created between individual amino acids .The whole thing becomes very complex and is extremely error-prone. A wrong binding and the protein is non-functional. That is why there are several quality controls in our body that are supposed to ensure that everything is correct.
One of these quality controls are the chaperones. If someone is interested in England and language, then the meaning is quite often already clear. A little tip: it is very commonly used in the successful Netflix series "Bridgerton".
A chaperone is therefore an older woman who accompanies a younger one as a protector. A lady of propriety from England is then something like a propriety protein in the body. It helps new proteins to fold or damaged proteins to refold correctly.
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 alone in 2022. The work of the researchers from Bael is considered one of the most significant in recent years, because with the help of artificial intelligence, medicines and vaccines can be developed faster in the future
Loss of proteostasis – how do misfolded proteins occur?
Between 40 and 80% of all proteins are misfolded and require assistance. That is an enormous number.There are several factors that can negatively affect protein structure. These include ultraviolet radiation, heavy metals, heat, or ethanol. Especially with food or dietary supplements , it is therefore important to pay attention to corresponding certificates.
If the stabilization or restoration of the correct folding is not successful, the proteins are initially unusable and must be disposed of. What is handled by the waste incineration plant or the recycling center for us is done in the body by the proteasome. Together with a small protein called ubiquitin (Ub), the damaged molecule is marked multiple times, broken down, and disassembled into individual amino acids.
All these systems work in coordination for the restoration or disposal of misfolded proteins. This enables the body to prevent the accumulation of damaged components and ensure the continuous renewal of intracellular proteins. Another building block of our intracellular waste disposal is the autophagy, which we will introduce to you as the 12th Hallmark of Aging.
So much for the theory.In practice, there is unfortunately 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 by 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. An increase in the concentration of heat shock proteins is associated with a number of health-promoting benefits.
In a study, researchers were able to show that higher levels of Hsp70 could lower the inflammatory mediator Interleukin-10.This explains to researchers why sauna can help with inflammations such as arthritis.
Wrinkles – top in proteins, flop in old age
While wrinkles in our perception are a sign of age and thus rather negatively connoted, it is quite the opposite with proteins, as we now know.
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 continuously increasing due to the rising life expectancy.
The production of chaperones in response to stress is significantly reduced with age. Studies on animal models support the hypothesis that the decline in chaperones is causally related to a decreased lifespan. Genetically modified worms and flies, for example, which produce chaperones in greater amounts, are particularly long-lived. In long-lived mouse strains, a upregulation of certain heat shock proteins has also been found.
Additionally, studies on mammalian cells show that an upregulation of SIRT1 improves the heat shock response. SIRT1 belongs to the gene family of sirtuins, which are referred to as longevity pathways due to their numerous effects related to aging.Many other experiments and studies have provided scientific evidence for the connection between chaperone levels and lifespan – naming all of them would exceed the scope of this article.
Proteostop
Medical and biological research has already done a lot of work in clarifying the issue of proteostasis, but are there already concrete approaches to stop 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, the pharmacological 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 ladies of our body are therefore not only gentlewomen but also fighters on the front lines against aging.
Another point of approach is the proteasome and other mechanisms that serve to degrade damaged proteins, as studies show that the activity of these systems decreases with age. This was achieved with selected enzymes that have exerted their effect within this complex signaling pathway.
Supplementation with Spermidine activated, for example, the autophagy system. This refers to the degradation of damaged cellular structures (such as proteins). Simplified, autophagy functions similarly to the proteasome we know.
