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# Getting Proteins Right to Live Longer

## The accuracy of protein synthesis appears to be a critical part of lifespan in model organisms.

Changing a single amino acid in a single protein boosts the fidelity of protein synthesis, and that is enough to increase lifespan in a variety of organisms, according to new research [1].

The loss of proteostasis is one of the hallmarks of aging. However, much of the research on the topic has focused on areas such as degradation, with less attention having been given to how differences in protein synthesis could affect aging. This is particularly striking because DNA mutations have gotten a lot of attention despite being several orders of magnitude less common than errors in proteins.

The translation of DNA into proteins (via mRNA) is a complex, highly orchestrated process involving a panoply of molecular players. Mutations in ribosomal proteins involved in the process have been shown to affect the fidelity of translation, and there’s even some evidence that they affect lifespan, though most of the work has been done in single-celled organisms. Prompted by this, an international team of researchers decided to investigate the consequences of a similar mutation in multicellular creatures.

The team focused on the ribosomal protein RPS23 because of its role in proofreading during protein synthesis. Examining the RSP23 sequence in a wide range of organisms revealed that the 60th amino acid in the protein was nearly entirely conserved throughout evolution, in organisms from archaea to eukaryotes. The only exceptions were in archaea that live in extremely hot environments, where the amino acid had switched from a lysine to an arginine. Given that such extreme environments can lead to errors in protein synthesis and folding, it seemed reasonable to hypothesize that the lysine-to-arginine switch might improve the accuracy of the process.

#### Correction at a cost

The team tested this idea by inducing the same mutation in model animals, such as fruit flies, yeast, and nematodes. They found that the mutation increased protein translation accuracy and, intriguingly, that it prevented the increase in translation errors normally seen with age. It also made the test animals more resistant to heat stress and increased their lifespan.

These findings prompted an obvious question: if this change is so beneficial, why is it confined to one group of organisms instead of being spread throughout the tree of life? The researchers hypothesized that the benefits were offset by negative trade-offs. Consistent with this, they found that the mutant yeast colonies were smaller than their wild-type counterparts. Likewise, the mutant nematodes and fruit flies developed more slowly than wild types, and behavioral measurements in nematodes showed that the mutation decreased size-related behaviors but not other behaviors. In other words, the increase in accuracy comes at the cost of decreased or delayed growth and reproduction. In extreme conditions, the boost in accuracy is worth it, but in other contexts, the slower, more accurate mutants would lose out to their faster-breeding lysine-carrying kin.

Finally, the team tested whether longevity drugs such as rapamycin might act by increasing translation fidelity. They found that pharmacological interventions like rapamycin do reduce translation errors, but rapamycin nevertheless increased the lifespan of the mutant organisms. This suggests that increased translation fidelity is only part of the anti-aging activity of rapamycin, and it also demonstrates that drug treatments that improve translation accuracy can increase lifespan, holding out hope that these findings could be used as the basis for developing novel longevity therapeutics.

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..

#### Conclusion

This is an elegant and intriguing study. It’s particularly interesting to see that tweaking protein translation can significantly affect lifespan in multicellular organisms given the recent claim that the evolution of the hallmarks suggests that efforts should focus on the “metacellular hallmarks”. This work demonstrates that addressing the simpler mechanisms can help, and it highlights the value of focusing on ways to improve protein translation accuracy and fidelity.

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#### Literature

[1] Martinez-Miguel, VE, et al. Increased fidelity of protein synthesis extends lifespan. Cell Metabolism (2021), doi: 10.1016/j.cmet.2021.08.017
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#### Sedeer el-Showk

Sedeer became a professional science writer after finishing a degree in biology. He also writes poetry and sff, and somehow juggles an ever-growing list of hobbies from programming to knitting to gardening. Eternal curiosity and good fortune have taken him to many parts of the world, but he’s settled in Helsinki, Finland for the moment. He hopes he’ll never stop learning new things.
##### 1 Comment
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1. ###### October 12, 2021

Bad comparison between error rates. Martinez-Miguel et al. open their article by stating:
“ In stark contrast to the well-established effect of DNA mutations on multi-cellular organismal aging and disease (Garinis et al., 2008), the role of translation errors is far less studied and understood. This is despite mistranslation being the most erroneous step in gene expression. The frequency of protein errors is estimated at 10^{-3} to 10^{-6}, depending on the organism and codon. (Ke et al., 2017; Kramer et al., 2010; Salas-Marco and Bedwell, 2005; Stansfield et al., 1998). This is several orders of magnitude higher compared to DNA mutations, which are estimated at 1.4 \times10^{-8} per nucleotide site per generation for base substitutions in humans (Lynch et al., 2016).”

These authors are comparing apples and oranges. The authors are concerned with the importance of errors in primary structure of proteins and in particular exploring the source of these protein errors arising from the translation step of protein synthesis. They are implicitly concerned about somatic cells for this to be relevant to ageing. A mutation in the somatic cell nuclear or mitochondrial DNA would also ultimately lead to an error in protein primary structure. But the mutation rate cited by these authors, that $1.4 \times10^{-8}$ per nucleotide site per generation for base substitutions in humans, is a different beast altogether. It’s the value cited by in a paper entitle “Genetic drift, selection and the evolution of the mutation rate” \citep{Lynchetal2016} for the DNA mutation rate per generation in human germ cells. Somatic cell DNA mutation rate has been estimated by Zhang et al. \citep{Zhangetal2019} in human blood cells (B lymphocytes). They find interestingly that somatic mutations increase progressively with age from 463 per cell in newborn babies (apologies to the two babies that had their heals pricked for this study) to 3127 per cell in centenarians. If choose the rate of 2102 somatic mutations per cell that Zhang et al. found for 52 to 75 year-olds and further we assume these cells are typical and they sequenced both diploid sets with 6.2 billion base pairs, then the mutation rate is $3.7 \time 10^{-7}$ base pair per cell (already more than 20 times the mutation rate relevant for genetic drift — i.e. in the germ line passed between generations). But we are still comparing apples and oranges if we use this number. Multiplying by 3 base pair per codon we find $1.0 \time 10^{-6}$ codon errors per cell, i.e. about 1 in a million amino acids are likely to suffer from errors (not accounting for redundancy in the genetic code which would reduce this a bit). And since we are interested in comparison for rates of errors in proteins (I think anyway, we’ll get to the protein errors below), we should account for protein length. Apparently the median protein length in humans is 375 amino acids\citep{BrocchieriKarlin2005} (again, this only makes sense if we assume the blood cells studied by Zhang et al. are typical of all tissues) we arrive at a protein error rate of $3.8 \time 10^{-4}$ due to somatic cell nuclear DNA mutations. Suddenly we are very much in the ball park of the protein error rate due to translation cited.

Let’s have a closer look at the protein translation error. Are they talking about errors per amino acid or whole protein? And where did the data come from? Surely it’s all for humans, right? Recall Martinez-Miguel et al. cite 4 studies
“This is despite mistranslation being the most erroneous step in gene expression. The frequency of protein errors is estimated at $10^{-3}$ to $10^{-6}$, depending on the organism and codon. (Ke et al., 2017; Kramer et al., 2010; Salas-Marco and Bedwell, 2005; Stansfield et al., 1998). ”

Of these 4 studies , the last 3 studied yeast. In fact, Kramer et al. found in yeast errors vary by codon from a low of $4 \times 10^{-5}$ to a high of $6.9 \times 10^{-4}$ per codon and that error frequency is in general about threefold lower than in E. coli.
OK so if translation errors are 1000 times higher in a bacteria than in yeast, maybe we shouldn’t trust any of these numbers for humans. Fortunately the first study studied mammals, in particular compared several species of rodents and found that the rate of translation errors varied with the lifespan of the mammal. The longest lived rodents were the Nake mole rat and Castor canadensisat 32 and 24.3 years. I had trouble determining an exact error rate from their study (maybe it’s buried in their study somewhere, I admit I’ve already spent too many hours trying to track this down) but what I do take from their study is that the result depends upon the species and varies significantly with species lifespan. So what is the translation rate error per codon or protein in human cells? Does it depend so strongly upon age as the somatic cell nuclear DNA mutation rate?

To be clear, I am not at all saying that the study of Martinez-Miguel et al. is irrelevant. Au contraire, I’m very glad to see researchers broadening the net in the search to make sense of the ageing process. And their findings are truly fascinating. But I strongly regret that ageing research lacks the rigor, careful argumentation and clear presentation that I find in other areas of science, such as astrophysics.

I very much appreciate the brief summary of what Martinez-Miguel et al. present. You’ve selected a very interesting study highly worthy of our attention. I do wish to plead for a more critical assessment.

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