Brain aging mainly manifests as decreased memory capacity, reduced learning speed and reduced cognitive flexibility. But what molecular mechanisms underlie these symptoms?

So far, studies have identified several molecular processes such as DNA mutations, reduced RNA and brain protein synthesis, loss of soluble RNA and epigenetic changes. These phenomena occur simultaneously, and it is to date unclear which initially causes brain ageing and which is a subsequent effect.

According to a study conducted by an international team coordinated by the Scuola Normale with its Bio Laboratory Bio@SNS, the Leibniz Institute on Aging and Stanford University, a stalling in protein synthesis could be the first cause of brain ageing. The study was done in collaboration with the Anton Dohrn Zoological Station.

The UniTS Laboratory of Synaptic Homeostasis, which specialises in the study of brain regulation mechanisms during aging, has also contributed to this important work. The team led by Eugenio Fornasiero provided support for a detailed analysis of protein turnover in the brain.

The insight behind the study was obtained by observing the process of brain aging in the Nothobranchius furzeri (turquoise killifish), a small East African fish known for its very short lifespan in captivity (less than one year). Professor of Physiology Alessandro Cellerino, one of the study coordinators, had the brainwave of introducing the fish as a new model for the study of aging 25 years ago at the Scuola Normale. The very short lifespan of these small fish and the fact that their brain physiology is similar to that of all vertebrates greatly reduces the time and cost of ageing studies, without losing relevance for humans.

"We observed that as age progresses, ribosomes no longer flow freely but stall or lock in precise positions along RNA strands, generating incomplete proteins,” Cellerino explains. "These proteins, 'lost in translation', have a low solubility and therefore tend to precipitate inside the cell. The surprising finding is that not all RNAs are subject to this phenomenon in the same way: the proteins affected are those that comprise the ribosomes themselves, which therefore decrease in number and generate a vicious cycle.

The stalling of ribosomes, therefore, could be the mechanism linking the different molecular changes related to brain ageing.

The next step will be to use Killifish to test whether treatment with substances capable of reducing the stalling of ribosomes is sufficient to slow cognitive impairment. If this were confirmed, new avenues in the medical field would be opened up.”

Published in Science, the paper is entitled ‘Altered translation elongation contributes to key hallmarks of aging in the killifish brain.’