Translation is the process by which cells manufacture many copies of a protein from one messenger RNA sequence encoding that protein. This takes place in one of the many ribosomes present in the cell, after which a newly assembled protein is folded within the endoplasmic reticulum. Translation is important, and so has evolved to be highly efficient. Errors nonetheless occur, and are corrected by various processes that identify broken, misfolded, and other problem proteins and ensure they are broken down for recycling. Those quality assurance processes have also evolved to be highly efficient. Correctly formed proteins are necessary for cell function, and malformed proteins will tend to cause harm in proportion to their numbers.
Nonetheless, different species exhibit different degrees of efficiency in translation. A range of evidence suggests that these differences provide a meaningful contribution to species life span. For example, naked mole-rats live as much as nine times longer than similarly sized mice, and exhibit exceptionally low rates of translation error. Like most long-lived species, however, naked mole-rats also exhibit many other adaptations that probably influence longevity, and it is ever a challenge to determine the degree to which each each of these distinct characteristics contributes to slowed aging and increased life span.
In today's open access paper, researchers provide an interesting demonstration of the effects of differences in translation error rates on longevity. They used yeast as a model. It is possible to produce thousands of distinct genomes by crossing two yeasts, and people have done this. It is a fairly standard approach if wanting to use small differences in similar organisms as a way to illuminate some aspect of cellular biochemistry. From that starting point, the researchers identified a gene variant that has a sizable effect on translation error rate, and also increases life span by 8%. Yeast, being a lower form of life, tends to respond to interventions with a large change in lifespan; one would expect effect sizes in mice to be smaller, but the next thing to do would be to try a similar genetic change in a mouse lineage and see what results.
Translational fidelity and longevity are genetically linked
A number of theories have been proposed to explain aging from various perspectives. One of the most influential of them is the Error-Catastrophe Theory of Aging, first proposed in 1963. According to this theory, errors that inevitably occur during messenger RNA (mRNA) translation will, sooner or later, happen to the proteins involved in the molecular machinery of translation. Consequently, translational fidelity will be reduced, resulting in a vicious circle towards even more errors, thus the decline of physiological function and eventually the death of the organism.
Based on the Error-Catastrophe Theory of Aging, there are three major directions to test the role of translation error in aging. First, the theory predicts that aged cells will produce more erroneous proteins than young cells. However, this has not been supported by a large body of experimental results from a variety of organisms. Second, the theory predicts a correlation between longevity and translational fidelity, which has been demonstrated by comparisons across species. A third prediction of the theory is that longevity should change accordingly as translational fidelity is manipulated. Early experiments in this direction, in which streptomycin was used to enhance translation error rates, had largely negative results. But more recently, some positive results have been obtained when paromomycin or mutant ribosomal proteins are used to increase translation error rate. While the use of specific antibiotics or artificial mutations might not reflect the natural conditions, these findings demonstrated that increased translational fidelity can indeed enhance longevity, and prompted renewed interest in the theory.
Measuring the lifespan and translational fidelity of a panel of BY x RM yeast recombinant haploid progenies, we validate the fidelity-longevity correlation. Genome-wide quantitative trait loci (QTL) analyses reveal that both fidelity and longevity are most strongly associated with a locus encoding vacuolar protein sorting-associated protein 70 (VPS70). Replacing VPS70 in BY yeast by its RM yeast allele reduces translation error by ~8.0% and extends lifespan by ~8.9% through a vacuole-dependent mechanism. These results collectively demonstrated the genetic basis for the correlation between translation error and aging, which strongly support the role of translational fidelity in intra-specific longevity variations.
View the full article at FightAging
