Fewer Translation Errors Correlates with Greater Species Longevity in Rodents

Here, researchers provide evidence for a correlation between the rate of errors in translation, a step in the process by which proteins are produced from their genetic blueprints, and species longevity. Infrequent errors in the creation of proteins may be only a short-lived form of damage, as a low level of defective proteins should be recycled rapidly. It is quite possible that a higher error rate is an evolutionary consequence of short life spans, rather than vice versa. If a species is short-lived because it fills an environmental niche characterized by aggressive predation, for example, then evolution will not tend to produce a large investment in repair and systems integrity. Where such systems did exist in ancestors, they are lost in the absence of selection pressure to maintain them in the face of random mutational change. Still, the correlation is there to consider.

The error catastrophe theory of aging was proposed in the 1960s. According to this model, the aging process results from errors in mRNA translation that reduce the fidelity of the protein-translating enzymes leading to increasingly inaccurate protein synthesis, terminating in functional decline, and, ultimately, the death of the organism. This theory, for the first time, proposed that translation fidelity plays a major role in aging. The error catastrophe theory has been challenged by a number of studies in the 1980s. A major caveat of these studies, however, is that many of them were conducted in vitro following ribosome isolation. As the aging process affects entire cellular networks, isolated proteins or other cellular components may not fully recapitulate this in vivo process.

Experimental models where translation fidelity was experimentally perturbed displayed shortened lifespan and susceptibility to disease. For example, mutations in tRNA genes and tRNA processing enzymes have been linked to various human diseases. These studies underscore the importance of translation fidelity for maintaining organismal health. However, to prove that a process controls aging and longevity, ideally one would have to improve this process and show that it leads to lifespan extension. In the last decade, it was established that modulating the translational machinery can extend lifespan in a variety of organisms. Inhibition of the highly conserved target of rapamycin (TOR) pathway by mutations or chemical inhibitors such as rapamycin results in downregulation of protein synthesis and lifespan extension. The mechanisms explaining the life-extending effects of TOR inhibition are not fully understood, but most evidence points toward preferential translation of specific transcripts involved in stress response, rather than improved fidelity of translation. This leaves an open question whether translation fidelity plays a role in aging, and whether it is possible to improve translation fidelity.

A study by our group showed that the longest lived rodent, the naked mole rat (NMR) has significantly increased translational fidelity in comparison to a short-lived mouse. To examine the role of translational fidelity in aging, we tested whether translational fidelity co-evolved with species maximum lifespan. We examined translation fidelity in rodent species with diverse maximum lifespan ranged from 4 to 32 years. We found a strong correlation between the frequency of mistranslating the first and second codon positions and the maximum lifespan in 16 rodent species. This correlation remained significant after phylogenetic correction by the method of independent contrast, indicating that translation fidelity co-evolved with longevity. The fidelity of mistranslation at the third position and the misreading of a stop codon did not correlate with maximum lifespan, possibly due to the wobble effect at the third codon position, and to extremely low frequency of misreading the stop codon in all species. These results provide evidence that translation fidelity is an important factor in determining species lifespan.

Link: http://bit.ly/2tBFFnk



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