Haste makes waste: The significance of translation fidelity for development and longevity

Abstract

We highlight Martinez-Miguel et al. (2021), which demonstrates that an amino acid substitution in RPS23 found in thermophilic archaea contributes to increased translation fidelity, lifespan, and stress response but slows development and reproduction in other organisms.

Particular forms of archaea are the most extreme of all extremophiles, with some living in the frigid environments of Antarctica and others living in the boiling acidic springs of Yellowstone. How do these organisms survive such harsh environments? What do they sacrifice to live in these conditions? What do they gain? These species develop certain adaptations that make survival in these conditions possible, either to avoid damage to their systems or to develop advantages to help them survive the harms they might endure from their environment. Some forms of thermophilic archaea possess the genetic makeup to survive their harsh habitat. Given the association between increased stress resistance and longer lifespan, genetic changes that enhance survival under such harsh conditions may provide key insights into how to increase lifespan and extend healthspan. In their article, Martinez-Miguel et al. (2021) hypothesize that the protein RPS23 would be significant for this based on multiple previous reports, and they embarked on a phylogenetic analysis of this protein across multiple organismal kingdoms. They found that a particular amino acid substitution in the protein RPS23 that is typically only present in sub-groups of thermophilic and hyperthermophilic archaea improves the fidelity of protein translation. In most classes of organisms, this residue of interest is a lysine, but when changed to arginine (a rare event that is only found in these archaea groups), translational errors are reduced, stress response proteins are expressed more, and survival and healthspan can be increased in yeast, worms, and flies.

The evolutionary causes for their findings may be rooted in the “error catastrophe” theory, which suggests that mistakes in amino acid incorporation would increase exponentially over time, leading to the aging of the organism (Orgel, 1963). Although this theory is no longer accepted in its original form, efficient and error-free protein translation has been further proposed as a requirement for longer life (Scheper et al., 2007). Decline in translation accuracy due to flawed machinery or mutations can result in the synthesis of malformed proteins, thus contributing to improper function and potentially toxic protein aggregation (Vermulst et al., 2015). This is further corroborated by the finding that translation efficiency correlates with lifespan across multiple species (Ke et al., 2017), though the evolutionary rationale and mechanisms by which this is regulated are continued areas of study. One key factor driving protein synthesis is the target of rapamycin (TOR), which plays essential roles in translation via the phosphorylation of S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), among other mechanisms. Inhibition of TOR via pharmacological compounds, genetic manipulation, or dietary restriction has repeatedly demonstrated longevity-inducing effects (Kapahi et al., 2010). In part, this increase in lifespan by inhibition of TOR has been ascribed to increased translation fidelity (Conn and Qian, 2013). Similarly, factors that regulate the stages of protein synthesis, such as protein elongation factors (Xie et al., 2019) or ribosomal subunits (Steffen et al., 2008), have also been shown as targets for lifespan extension (Gonskikh and Polacek, 2017). It is clear that there is an intimate relationship between translation efficiency and lifespan, and that TOR plays an essential role in this regulation.

Martinez-Miguel et al. (2021) demonstrate that a switch from lysine to arginine in RPS23 in worms and flies also exhibited slower development with reduced cell division in yeast, suggesting that this improvement in translational fidelity was accompanied by reduced growth. They further demonstrated that compounds known to extend lifespan via TOR inhibition like rapamycin, torin 1, and trametinib, also reduce the number of translation errors, suggesting a “less is more” outcome with regards to fidelity. Interestingly, in yeast and flies, this switch from lysine to arginine in RPS23 did not extend lifespan further in organisms treated with rapamycin. In worms, rapamycin did not increase lifespan further in animals with the arginine in RPS23 but did increase lifespan in animals with the lysine. The findings from this study demonstrate not only how alterations in protein-coding mechanisms can influence longevity through translation accuracy, but also raise questions about how genetic variants across species of different kingdoms might have evolved for different environments. It stands to reason that these bacteria that naturally possess the long-lived allele do so because of the elevation in heat stress response proteins that are translated, a requirement for thermophilic environments. However, is there a cost for this adaptation? A potential trade-off for this adaptation proposed by the authors is the effect on slowed development time, thus resulting in a longer time to reach sexual maturity (Figure 1). From an evolutionary standpoint, this fits nicely with an antagonistic pleiotropy whereby processes that slow growth and reproduction tend to extend lifespan (Williams, 1957), though this is not beneficial for wild animals that do not live as long and thus must reproduce earlier in life.

Figure 1. The intricate balance between development and lifespan is dictated by translation fidelity.

RPS23^K60R variant and TOR inhibition are examples of antagonistic pleiotropy that enhance translational fidelity to reduce growth but increase somatic maintenance. This shifts animals to reduce reproduction, increase development time, extend lifespan, and increase stress response.

A key to understanding the limits of our mortality may come in the form of understanding our evolution. Genetic and proteomic variations across species can provide important insights into longevity-inducing mechanisms, similar to the species of thermophilic archaea which highlight translation fidelity. Garnering insights into how other species have improved their chances of survival can provide valuable information toward identifying potential targets for enhancing human lifespan.