3/8/2022 5:30:00 AM
New work “is the first to show that an increase in translation errors causes shortened life span and accelerated aging in mammals.”
Mice with sloppy protein making machinery grow old faster, study finds
Cells are continually cranking out new proteins, but like car factories, they produce some lemons. A study of mice now suggests these defective proteins speed aging, bolstering an idea first proposed 60 years ago. The new paper “fills a critical gap” and “allows us to say that protein damage is an accelerant of aging,” says molecular biologist Richard Morimoto of Northwestern University, who wasn’t connected to the study.
The mouse research focuses on the importance of ribosomes, the cell’s protein assembly lines. When these organelles receive instructions from the nucleus to build a particular protein, they stitch together amino acids in a specific sequence. But the process, known as translation, isn’t perfect. Every so often, a ribosome installs the wrong amino acid. Such mistakes can hamstring a protein or cause it to fold incorrectly and become toxic for the cell.
In 1963, chemist Leslie Orgel proposed that translation errors such as these promote aging. Orgel’s hypothesis held that mistakes would accumulate at an accelerating rate until the cell dies, but researchers found scant support for this error explosion. Nonetheless, some recent evidence suggests translation miscues contribute to aging. For instance, lab mice, which typically don’t live longer than 2 or 3 years, make more mistakes during protein synthesis than do the African rodents called naked mole rats, which can survive up to 30 years. And when researchers genetically tweaked yeast, fruit flies, and nematodes to greatly increase their ribosomes’ accuracy, the modified organisms headtopics.com
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lived up to 23% longer than normal. To test whether slip-ups during protein synthesis propel aging in mammals, molecular biologist Erik Böttger of the University of Zurich and colleagues genetically engineered mice to have error-prone ribosomes. The change led to more mistakes during translation. One type of gaffe, in which cells manufacture proteins that are too long, was twice as common in the altered mice as in control rodents.
When mice with error-prone ribosomes were young, they appeared healthy. But by the time the animals were 9 months old, roughly equivalent to humans in their 30s, they started to look and act old. Their fur began to turn gray and fall out. They developed cataracts, hunched postures, and abnormally curved spines. Like older humans, the mice began to lose their body fat and muscle. Their physical performance also declined. Compared with their normal counterparts, the modified rodents couldn’t swim as fast and were more sedentary.
Along with these failings, the animals showed molecular signs of faster aging. Their proteins carried more damage from reactive oxygen species, destructive byproducts of metabolism linked to aging. Their telomeres, the chromosome caps that shrink over time, also shortened faster than in normal rodents.
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And reducing the accuracy of protein synthesis clearly cut the rodents’ life span. The altered mice were about before they reached 18 months of age than their unmodified peers, the researchers report today inScience Advances. The study indicates that inaccurate protein synthesis “is a key player in aging,” Böttger says. Now, he adds, “You can think about strategies for healthy aging,” including developing drugs that would increase the accuracy of translation.
The work “is the first to show that an increase in translation errors causes shortened life span and accelerated aging in mammals,” says Jiqiang “Lanny” Ling, a molecular geneticist and biochemist at the University of Maryland, College Park, who wasn’t connected to the study. But researchers still need to confirm that sloppy protein synthesis drives age-related problem in humans, such as gimpy knees and failing hearts. “The next burning question,” he says, “is how does it lead to aging?”
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