Getting to the root of aging through ribosomes

Aging leads to deterioration of cellular fitness and loss of optimal protein function. The mechanisms underlying how aging causes the accumulation of proteins are not fully understood. Using models of human aging, yeast and roundworms, researchers at Stanford University traced this problem in aging to the age-dependent impairment of the machinery that produces new proteins.

The results were published in the journal temper nature In a paper titled “Aging Exacerbates Ribosome Inactivation Inactivation of Proteostasis Challenger.”

“Aging is accompanied by a decrease in cellular proteins, which underlie many age-related protein misfolding diseases,” the researchers wrote. However, how aging impairs the proteins remains unclear. As nascent polypeptides represent a significant burden on the proteasome emboli network, we hypothesized that altered translational competence during aging could help drive protein breakdown. Here we show that aging alters the kinetics of translation elongation in both Certain types are elegant And yeast yeast. This exacerbated ribosome pausing at specific loci in yeast and archaea, including multibase extensions, resulted in increased ribosome collisions known to induce ribosomal quality control (RQC).

Through a combination of experiments and analysis of computational data, the researchers found that ribosome function deteriorates with age in both organisms. The increased load of defective proteins with age is overshadowed by the protective QC protection that would prevent protein aggregation.

We have learned that protein buildup with age is a problem associated with many diseases. Currently, treatments are trying to address them by trial-and-error testing,” said Dr. Kevin Stein, the paper’s lead author and former postdoctoral researcher in Friedman’s lab. “Referring to the basic biology of these diseases, and understanding the mechanisms that cause them, can help us take action. Better decisions about which treatments can be effective before they are tested.”

“One of the most vulnerable and most important times in the life of a protein — where it is most susceptible to misconfiguration — is when it is synthesized,” said Judith Friedman, Ph.D., professor of biology and genetics at Stanford University.

The researchers used a technique called ribosome profiling, which allowed them to see how ribosomes move on messenger RNA during the translation process. They note that ribosomes in older cells periodically move more slowly and decreases in ribosome performance are in line with increases in the aging-dependent assembly of unfolded proteins.

“There is a two-fold situation where aging leads to increased pauses and increased ribosome collisions, but the cell loses a safety net to deal with,” Stein explained.

Researchers hope with their findings regarding aging in yeast, elegans, And other living things would also translate to humans.

“This is only the beginning of a very fascinating future,” said Fabian Morales Polanco, PhD, a research co-author and postdoctoral scientist in Friedman’s lab. “We’ve set a precedent for something new, and there are millions of questions – possibly hundreds of papers – that will follow.”

The authors conclude that, “Increased ribosome pausing, resulting in increased RQC load and nascent polypeptide assembly, critically contributes to proteosome dysfunction and systemic degradation during aging.”

Leave a Comment