Researchers at UCL and MRC London Institute of Medical Sciences have demonstrated that reducing naturally occurring errors in protein synthesis improves both health and lifespan in different model organisms. The findings, reproduced in yeast, roundworms, and fruit flies, are the first to demonstrate a direct link between fewer protein mistakes and longevity. The study also found that some drugs that are approved for human use, and which are known to have anti-aging properties, act to correct errors in proteins.

“We commonly hear about DNA mutations, which can cause cancer, and are considered one of the underlying causes of aging,” commented Ivana Bjedov, PhD, at UCL Cancer Institute. “However, mistakes in proteins which affect 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.” Bjedov is senior author of the team’s published paper in Cell Metabolism, which is titled, “Increased fidelity of protein synthesis extends lifespan.”

In what the authors called “stark contrast to the well-established effect of DNA mutations on multicellular organismal aging and disease,” the role of errors in protein translation is far less studied and understood, despite mistranslation being the most error-prone step in gene expression. “The frequency of protein errors is estimated at 10-3 to 10-6, depending on the organism and codon,” they wrote. This is several orders of magnitude higher compared to DNA mutations. And in fact, they continued, “Proteostasis disruption is a critical factor underlying aging and age-related diseases, with translation being one of its key determinants. Therefore, an improved understanding of the biological impact of translation errors in the context of organismal aging is very much needed.”

For their reported study, scientists investigated an evolutionary “hyper-accuracy” mutation, known as RPS23 K60R, found in the ribosomes—these are the cell’s protein producing factories—of hyperthermophilic Archaea, a single-celled organism that can live at extremely high temperatures. Using genome editing techniques, the team engineered a metazoan ribosome to carry the identical mutation (a single amino acid change) as the hyperthermophilic Archaea, and replicated its effect on protein synthesis in simple model organisms, namely the fruitfly Drosophila melanogaster, yeast (Schizosaccharomyces pombe), and the roundworm Caenorhabditis elegans.

“We hypothesized that improving fidelity of protein synthesis could be an anti-aging intervention in multicellular organisms,” they wrote. “Here, we investigated the physiological consequences of directly mutating a single evolutionarily conserved residue in the decoding center of the ribosome and examined for the first time in metazoan species the effect of increased protein synthesis fidelity on aging.”

The scientists’ analyses confirmed that the organisms’ proteins had fewer errors and, as a result, they became heat resistant and lived longer. “When introduced into eukaryotic RPS23 homologs, this mutation leads to accurate translation, as well as heat shock resistance and longer life, in yeast, worms, and flies,” the team stated. First author, Victoria Eugenia Martinez-Miguel, PhD, at UCL Cancer Institute, 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 center reduces protein synthesis mistakes and improves an organism’s stress resilience and longevity.”

In addition to the reengineered ribosomes, the researchers found that some drugs approved for human use can also reduce mistakes in proteins. “Great interest in the biology of aging stems from a possibility to improve health in the elderly by mimicking the effect of longevity mutations on organismal physiology through pharmacological approaches,” they stated. Interestingly, these drugs, rapamycin, torin, and trametinib, are also known to be anti-aging drugs. They affect the cell’s ability to sense nutrients and therefore when applied in small quantities can have a similar effect as calorie restriction, a known pro-longevity treatment. The new study suggests that reduction of protein errors is a unifying mechanism of anti-aging drugs that could contribute to healthy aging.

“ … we show that anti-aging drugs such as rapamycin, Torin1, and trametinib reduce translation errors, and that rapamycin extends further organismal longevity in RPS23 hyperaccuracy mutants,” the scientists stated. “Our work demonstrates that increased translation accuracy can be achieved pharmacologically and argues for screening of compounds with the potential to reduce protein errors during aging.”

Co-corresponding author Filipe Cabreiro, PhD, at the MRC London Institute of Medical Sciences, further noted, “This is the first study in a metazoan organism to reveal that fewer mistakes in proteins can prolong health and longevity; we expect our results on yeast, worms, and flies to be extended to mammals, which could potentially lead to treatments for improved health in the elderly.” And as the authors concluded, “Collectively, these findings advocate for the investigation of therapies aiming at increasing translation fidelity in the context of aging and age-related diseases, particularly neurodegenerative diseases that are primarily affected by deterioration of proteostasis.”

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