Researchers at the MRC London Institute of Medical Sciences (LMS) and University College London (UCL) might have unlocked the secret to healthy ageing by showing prevention of protein errors extends lifespan.

Archaea, a single-celled organism is known to tolerate extremely high temperatures due to a single point mutation in its ribosomes, the machinery required to synthesise proteins. This mutation enhances the performance of ribosomes, making them less error prone.

LMS and UCL researchers genetically engineered these mutated ribosomes to observe their impact in more complex organisms, such as yeast, worms and flies. They found each organism displayed fewer protein production errors and that as a result lived up to 23% longer.

The novel findings, published in Cell Metabolism, are the first to demonstrate a direct link between fewer protein mistakes and increased life span.

Dr Victoria Eugenia Martinez Miguel, member of the Molecular Biology of Cancer group at UCL Cancer Institute and co-author of the paper said: “The process of making proteins is not error free – ribosomes make mistakes. We have shown, for the first time, that changing a single amino acid in the ribosome decoding centre reduces protein synthesis mistakes and improves an organism’s stress resilience and longevity.”

It is well known that changes to DNA contribute to ageing and disease. However, despite the frequency of protein production errors being significantly higher than the average DNA mutation rate, the impact of protein mistakes on health is less understood.

To investigate further, the researchers looked at the impact of rapamycin, torin, and trametinib in yeast, worms and flies. These drugs are commonly used to treat cancer in humans and in low concentrations are known to have anti-ageing properties. So far, they have been shown in the lab to induce a calorie restrictive environment through blocking cell’s ability to sense nutrients. However, their shared mechanism for promoting longevity is unknown.

The researchers showed small quantities of rapamycin, torin, and trametinib reduced protein errors and extended lifespan. This suggests reduction of protein errors is a unifying mechanism of these anti-ageing drugs, and that promoting improved protein synthesis could contribute to healthy ageing.

Dr Ivana Bjedov, head of the Molecular Biology of Cancer group at UCL Cancer Institute and fellow author of the paper said: “We commonly hear about DNA mutations, which can cause cancer, and are considered one of the underlying causes of ageing.

“However, mistakes in proteins and their effect on organismal health are largely neglected, despite the fact that errors introduced during synthesis of new proteins are much more frequent than mutations made during DNA replication.

“For this study we therefore focused on protein errors, and we questioned if fewer mistakes in proteins improve health.”

Professor Filipe Cabreiro, head of the Host-Microbe Co-Metabolism group at the MRC LMS and fellow author of the paper concluded: “This study is the first to show decreasing protein errors extends lifespan. With an ageing population and many people experiencing ill-health as they grow older, it is more important than ever that we be able to facilitate healthy ageing.

“Our results pave the way for identifying novel interventions to do exactly that.”

‘Increased fidelity of protein synthesis extends lifespan’was published in Cell Metabolism on 14 September 2021.