A genetic tweak that improves the accuracy of protein synthesis can lengthen an organism’s lifespan, according to a paper published this week (September 14) in Cell Metabolism. The results were consistent across three species—the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the yeast Schizosaccharomyces pombe—suggesting that building better proteins may be linked to longevity in other species, too.
“The work is very convincing, very compelling, and I think it addresses a really important outstanding question in the field of aging: What are the best ways to look after our proteins and help ourselves to function better for longer?” says protein researcher John Labbadia of University College London who was not involved in the research.
As an organism ages, the efficiency and accuracy of its cellular processes deteriorate. For example, protein production, folding, and degradation all decline in quality, such that loss of protein homeostasis (proteostasis), is “a major hallmark of aging” and age-related diseases, says molecular biologist Patricija van Oosten-Hawle of the University of Leeds who did not participate in the research.
In the case of protein production—the translation of RNA code into peptide chains—the prevalence of errors “correlates positively with lifespan,” University of Rochester aging researcher Vera Gorbunova, who was not a part of the research team, writes in an email to The Scientist. However, “evidence showing that one can take a short-lived organism and extend its lifespan by making translation more accurate was lacking,” she writes, adding that the new Cell Metabolism paper “provides this last missing proof.”
Within the protein factories of the cell, known as ribosomes, a protein called RPS23 is considered critical for translation accuracy. RPS23 was thus the obvious candidate when looking for ways to improve fidelity, explains molecular biologist Ivana Bjedov of University College London’s Cancer Institute. Her team studied RPS23 in species ranging from mammals to microbes. Within the protein, they found a region so highly conserved that, with the exception of some microorganisms that live in extremely hot environments, all species had an identical amino acid at the same position.
What are the best ways to look after our proteins and help ourselves to function better for longer?—John Labbadia, University College London
Bjedov wondered how the single amino acid change seen in thermophiles might affect translational accuracy. Her team introduced the change into the RPS23 gene of D. melanogaster and found that not only was translation accuracy improved, the flies also could survive higher temperatures and lived roughly 10 to 20 percent longer than control flies.
Bjedov’s collaborator, Filipe Cabreiro of the MRC London Institute of Medical Science, then introduced the same RPS23 amino acid change into C. elegans and got similar results. Further studies showed the amino acid change boosted translation accuracy and lifespan in yeast as well.
Finding consistent results across three species “makes you more reassured about what you’re seeing,” says Cabreiro. “It’s a robust observation.”
In the flies and worms, the life-extending mutation was associated with delayed development and reproduction—though ultimately, the numbers of progeny produced were similar to those of control animals. Similarly, in yeast, the mutation caused colonies to grow more slowly. It is not clear why the mutation caused this developmental delay. Translation rates between test and control animals appeared to be equivalent, as did other phenotypic traits. But the delay could explain why the mutation—which is otherwise seemingly beneficial—isn’t more widespread in nature, say the researchers.
Lastly, the team showed that, for the flies at least, the animals didn’t just have extended lives, but extended health—geriatric test flies could still be seen climbing the sides of their vials when similarly aged control flies no longer did so. Essentially, the test flies stayed youthful for longer.
An important next step for this research, says van Oosten-Hawle, would be “to look at what would happen in vertebrate model systems . . . how this [mutation] would affect longevity in mice, for example.” If such experiments show similar results to those in flies, worms, and yeast, the ultimate question, says Labbadia, would be, “how do we take this to humans?”