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Antiaging advice from single-celled creatures: Build better proteins

Microbes that live in hot springs and hydrothermal vents have long fascinated scientists for their ability to survive at temperatures exceeding 100°C. Now, these “extremophiles” are piquing interest for another reason: They may hold a clue to longevity in much more complex creatures, including people.

A genetic mutation that keeps the proteinmaking machinery of these tiny organisms from making mistakes can extend life span in flies, worms, and yeast engineered to have the same DNA change, researchers have found. The discovery suggests errors in protein synthesis may be an important driver of aging—and a target for future drugs that promote healthier aging.

The study is a “paradigm shift” in how we think about the causes of aging, says Vera Gorbunova, a molecular biologist at the University of Rochester who was not involved. “[It] improves our understanding of what’s important for longer life span.”

Many studies of the causes of aging and disease have focused on the accumulation of mutations in genes—the blueprints for a cell’s proteins and other molecules. Far fewer have looked at glitches in how each blueprint gets translated, which can create faulty proteins, says Ivana Bjedov, a biologist at University College London who led the new work. “I always felt sorry for little proteins.”

Key to translation is the ribosome, the cellular machinery that uses DNA’s instructions to assemble amino acids into proteins. When the ribosome makes a mistake, the resulting proteins may fold improperly, stick to other proteins, and sometimes cause damage to cells. (Misfolded or aggregated proteins are implicated in Alzheimer’s disease, Parkinson’s disease, and others.) Cells routinely find and dispose of faulty proteins, yet this maintenance process breaks down as we age.

So, would fewer translation mistakes increase longevity? Until the current study, “There was no proof that you could take an animal, improve translational fidelity, and make it live longer,” Gorbunova says.

Bjedov and her team looked to a part of the ribosome known to be critical for accurate translation: a protein called RPS23. While analyzing genetic data from species across the tree of life—from cows to gut microbes—the researchers found the same amino acid at a key position in this ribosomal protein. But there was an exception: Certain species of single-celled organisms called archaea that thrive in extremely hot and acidic environments had a mutation that replaced this amino acid with another.

Curious about the effects of this mutation, the researchers used the gene editor CRISPR to swap it into RPS23 genes of yeast, fruit flies, and the tiny roundworm Caenorhabditis elegans. Organisms with the mutation had fewer protein synthesis errors than unmodified controls. All three types of organisms could also survive at higher temperatures.

Most strikingly, the yeast cells, flies, and worms lived between 9% and 23% longer, the team reports today in Cell Metabolism. The mutants also seemed healthier as they aged: Compared with the control counterparts, older flies with the mutation were better able to climb and older modified worms produced more offspring.

That improving protein synthesis with just one mutation also increased life span is “a pleasant surprise,” says Vadim Gladyshev, a molecular biologist at Harvard Medical School. In studies of aging and longevity, he says, “It’s easy to make things worse [with a single mutation], but it’s much more difficult to make them better.”

It’s not clear how the mutation improves a ribosome’s accuracy, notes Filipe Cabreiro, an aging researcher at the Medical Research Council’s London Institute of Medical Sciences and a co-author on the paper. In the flies and worms, the genetic change doesn’t appear to slow down the overall rate of protein production, which previous studies have found can itself increase life span in some organisms.

Also unclear is why—if the mutation is so beneficial—only certain archaea species have it. One possibility: The genetic alteration comes with costs that might outweigh its benefits in less extreme environments. Hot conditions make proteins more prone to misfolding, which puts extra pressure on an organism to make accurate proteins, Cabreiro says. Putting the mutation into yeast, flies, and worms delayed their growth, he and his colleagues found. That could be costly if an organism needs to develop quickly to compete with other species for resources.

More accurate protein translation might explain the effects of drugs already known to extend life span in animals. One of the best studied, the antibiotic rapamycin, reduced translation errors in cells from flies, the researchers found. But when flies and yeast with the RPS23 mutation were given rapamycin, they still showed additional increases in life span, indicating the drug likely works via multiple mechanisms—not just improved translation accuracy. (In worms, rapamycin didn’t further extend the life span of RPS23 mutants, suggesting the drug’s effects vary by organism.)

Rapamycin isn’t widely considered a viable antiaging treatment for humans, in part because of the potential for side effects that can include immune suppression and risk of infections. But scientists may now be more motivated to screen other compounds for their effects on translation accuracy.

Cabreiro, meanwhile, plans to search for additional clues to longevity hidden in other species’ genomes. Hardy archaea pointed to one beneficial mutation, he says, but “that doesn’t mean that there aren’t other mutations that could [be] even better.”

Source: Science Mag