Protein synthesis and quality control in aging

Abstract

Aging is characterized by the accumulation of damage and other deleterious changes, leading to the loss of functionality and fitness. Age-related changes occur at most levels of organization of a living organism (molecular, organellar, cellular, tissue and organ). However, protein synthesis is a major biological process, and thus understanding how it changes with age is of paramount importance. Here, we discuss the relationships between lifespan, aging, protein synthesis and translational control, and expand this analysis to the various aspects of proteome behavior in organisms with age. Characterizing the consequences of changes in protein synthesis and translation fidelity, and determining whether altered translation is pathological or adaptive is necessary for understanding the aging process, as well as for developing approaches to target dysfunction in translation as a strategy for extending lifespan.

Keywords: aging; lifespan; proteostasis; ribosome; translation.

Figure 1

Age-related changes in protein synthesis and proteostasis. The main phases in the life of proteins are shown, with a focus on processes that change with age.

Figure 2

Age-related changes and lifespan modulating aspects of protein synthesis. The eukaryotic mRNA translation cycle is shown. During translation initiation, the 43S complex is formed (top). It harbors the initiator Met-tRNAi delivered by eIF2, which is inactivated upon amino acid starvation, UPR or other stress conditions. The 43S complex is loaded onto the capped mRNA 5’ end with the help of eIF4F, composed of the cap-binding protein eIF4E, a scaffold protein eIF4G, and a helicase eIF4A (not shown). The eIF4E-eIF4G interaction is inhibited by 4E-BP repressor proteins, which are activated during amino acid starvation when mTOR kinase is inactive. During elongation (right), cognate (or sometimes near-cognate) aminoacyl-tRNAs are delivered to the translating ribosome by eEF1A, followed by the peptidyl transferase reaction and eEF2-assisted translocation step (not shown). When the ribosome encounters a stop codon, translation termination occurs (bottom). At this step, the synthesized polypeptide is released by termination factor eRF1, delivered by eRF3 (not shown) and assisted by ABCE1. In some cases, however, the stop codon can be recognized by a non-cognate tRNA, leading to a readthrough event. At the final step (left), ribosome and deacylated tRNA should be removed from the mRNA (recycled) with the help of ABCE1, eIF2D and/or MCT-1/DENR proteins. Most of these events are affected by aging (light-green boxes) or linked to lifespan control (yellow boxes). Known positive and negative effects are shown by up and down arrows, respectively, while controversial or potential regulation is indicated by a question mark.

Figure 3

Molecular pathways modulating lifespan via control of the translation machinery. Components of the Ras/MEK/ERK signaling pathway are shown in yellow, those of the PI3K/Akt/mTOR axis in green, the ISR pathway in yellow, and the translation machinery components in grey [80,166,175,180].