This commentary on research results from last year is a good introduction to the topic of protein translation errors and their relationship with species longevity. Translation is one of the steps in the complex process of gene expression, in which genes are used as a blueprint to assemble proteins. Nothing is perfect and errors take place in translation, as everywhere else. Such errors are in effect a form of damage, causing issues for the cell until the broken protein is removed.
It is fairly well established that greater levels of the cellular maintenance processes of autophagy, responsible for removing damaged proteins, metabolic waste, and failing cellular structures, can result in slowed aging in a range of species. It sounds plausible that reducing the rate at which malformed proteins are produced would be beneficial for similar reasons, but this is harder to prove one way or another. The present laboratory is made up of the biochemistry of similar species with different life spans, translation machinery, and error rates. Unfortunately there are also many other differences: the study of aging is made very challenging by the inability to completely isolate mechanisms of interest, and dial them up or down without changing anything else.
When a protein is made by the cell, the genetic information is first decoded into mRNA, then this mRNA directs the protein synthesis. This is the flow of genetic information in cells from DNA to RNA to protein, the central dogma of molecular biology. The "error catastrophe" theory of aging, proposed in the 1960s, posits that translation errors decrease the fidelity of translation, setting in motion a vicious cycle of increasingly inaccurate protein synthesis, ultimately causing a failure of the gene expression machinery. However, in the 1980s, several approaches including enzymatic assays of protein synthesis errors, as well as analysis of proteins on 2D gels in aged animals and senescent cells, did not detect a significant increase in mistranslated proteins during aging and cellular senescence. These negative results were not consistent with the error catastrophe theory and errors in translation were largely discounted as being a contributing factor to aging.
Recent work brings the protein translation fidelity back into the spotlight of aging research. Importantly, the assays used to detect aberrant proteins in the 1980s had limited sensitivity to detect rare aberrant proteins, but in 2013 a new highly sensitive luciferase-based assay was developed to measure the rate of mistranslation in mammalian cells. This new assay showed that mouse fibroblasts make up to 10 times more errors in protein translation than fibroblast from the longest-lived rodent species, the naked mole rat. This was the first indication that a longer-lived species may evolve more accurate protein translation machinery. Later work compared the fidelity of protein translation in fibroblasts from 17 rodent species with diverse lifespans, and demonstrated that translation fidelity at the first and second codon positions correlates positively with species maximum lifespan, i.e. longer-lived species have more accurate translation.
The relationship between species maximum lifespan and translation fidelity shows that longer-lived species evolve more accurate protein synthesis. This, however, does not imply that protein translation errors lead to aging in individual organisms. This would be important to test using the new sensitive assays. In the future, a knock-in mouse model with luciferase reporters can be generated to examine the accumulation of mistranslated protein in different organs during aging. Mistranslated proteins may not impact cellular proteostasis significantly at young age, largely due to rapid protein turnover and efficient protein clearance. However, protein turnover rates, proteasome activity, and autophagy decline with age, making aged organisms more sensitive to errors in protein translation. Thus, even if protein translation fidelity does not change over the course of lifespan, long-lived species may require more accurate protein synthesis.