Ageing in the brain may be caused by a breakdown in protein production

We may have discovered a fundamental cause of cell aging that underlies many other aging processes in cells.

A study of the brain of freshwater fish called Killifish has shown that, as they age, protein manufacturing factories in cells are starting to blur while making a key protein class, causing a vicious decline cycle.

The discovery could lead to new ways of fighting brain aging, explains Alessandro Celerino at the Leibniz Institute on aging in Germany. “We are mainly talking about improving cognition or prevention of cognitive decrease, rather than increasing lifespan,” he said.

Protein manufacturing recipes are stored in DNA in our cells. When a protein is necessary, copies of these recipes are transcribed in a sort of molecule called mRNA.

The copies of mRNA are edited or sprayed, and sent to protein manufacturing factories called ribosomes, which bind to the mRNA molecules and move along them, reading the three -letters codons and translating them into a sequence of amino acids that make up the protein.

Normally, the more copies of mRNA, the more a protein is produced. But an increasing number of studies have shown that, as human cells are aging, this correlation is breaking down, so that the production of a protein can decrease despite any reduction in the quantity of mRNA.

Celerino and his team may have discovered why it happens by studying ribosomes in the brain of the kilfish as they age. The researchers used a technique which allowed them to take an instantaneous of the distance to which each ribosome had moved along the mRNA to which it was linked.

What they found is that, as the Killifish brain is aging, there were many more ribosomes linked to codons specifying the amino acids arginine and lysine that it would not be planned by chance. This means that ribosomes block these codons, which stopped production before the protein end.

Arginine and lysine are both positively loaded amino acids which are abundant in proteins which bind to DNA or RNA, which are both negatively loaded. This means that it is these DNA and RNA liaison proteins that are most likely to be affected by dropping out.

This is a problem, because these proteins exercise key functions, such as RNA manufacturing, splicing RNA, repair of DNA damage, etc.

“We know that with aging, there are DNA damage, there is less RNA production, there is less splicing, there is less protein production,” explains Celerino. “What we suggest is that this Ribosomes Stalling phenomenon connects all these different characteristics of aging.”

In addition, the ribosomes themselves contain RNA liaison proteins, he says. “There is therefore this vicious cycle by which there is staling on the mRNAs which code for ribosomal proteins, which leads to a production of ribosomes, which leads to a less synthesis of proteins.”

The big question is now whether stalling ribosomal occurs in the human brain. Earlier this year, Gene Yeo at the University of California San Diego has shown that RNA liaison proteins have exhausted in human neurons as they age. To this extent, his conclusions agree with thatrino, he says, but the cause is not yet clear. “We determine why RNA liaison proteins are modified.”

If the results apply to people, this could lead to new treatments for age -related brain conditions. In Killifish, the Stalling of Ribosomes also triggers an alarm signal which produces an inflammatory response. “The constant activation of this path causes chronic inflammation,” explains Celerino. “Chronic inflammation is a very important factor in aging, especially in the brain.”

There are experimental drugs that can block this signaling path and can therefore help avoid such conditions, explains Celerino.

“But for the lifespan, it is too early to really say anything,” he says. Indeed, the reason why ribosomes are starting to calculate on certain amino acids is not yet understood, and it is not clear either if the same dropout process occurs in all organs.