A Small Change in the Ribosome Reduces Protein Synthesis Errors and Modestly Extends Lifespan in Short-Lived Species

The ribosome is a cellular structure responsible for the translation stage of protein manufacture, in which proteins are assembled from amino acids according to the blueprint provided by a messenger RNA molecule. In today's research materials, scientists report that a small change in a ribosomal protein, found in heat-tolerant organisms, has interesting effects when introduced into short-lived laboratory species via genetic engineering. The outcome is a reduction in the error rate for protein manufacture, an increased heat tolerance, and a modestly extended life span.

It is worth noting that life span increases of this degree in very short-lived species such as yeast, flies, and worms should not be expected to appear in humans when the same approach is taken in our species. Very short-lived species have highly plastic life spans, particularly when it comes to approaches that improve the quality control of proteins in the cell, such as by increasing the efficiency of autophagy or proteasomal function in order to clear damaged proteins. As species life span increases, the effects of such interventions diminish. This is likely because longer-lived species have already evolved mechanisms that compensate in other ways, a necessary precondition for their longer life spans.

Nonetheless, this work on the ribosome, at the other end of the spectrum of protein quality control mechanisms, is interesting when considered in the context of the naked mole-rat, which lives nine times as long as similarly sized mammalian species. The much longer life span of the naked mole-rat is likely a result of the combination of many favorable differences in many areas of metabolism. That said, a few years ago it was found that this species has unusually efficient ribosomes, and therefore a lower rate of errors in protein manufacture. Today's results in flies and worms really only provide a starting point for debate over the degree to which the exceptional life span of the naked mole-rat is dependent on improved protein synthesis. While we should likely be leaning towards a smaller fraction of the overall effect rather than a larger fraction, there is clearly much more work to be accomplished on this topic.

Antiaging advice from single-celled creatures: Build better proteins

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. 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.

Researchers 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 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.

Increased fidelity of protein synthesis extends lifespan

Loss of proteostasis is a fundamental process driving aging. Proteostasis is affected by the accuracy of translation, yet the physiological consequence of having fewer protein synthesis errors during multi-cellular organismal aging is poorly understood. Our phylogenetic analysis of RPS23, a key protein in the ribosomal decoding center, uncovered a lysine residue almost universally conserved across all domains of life, which is replaced by an arginine in a small number of hyperthermophilic archaea. 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. Furthermore, 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. This implies a unified mode of action for diverse pharmacological anti-aging therapies. These findings pave the way for identifying novel translation accuracy interventions to improve aging.

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