Translational control in cell ageing: an update

Abstract

Cellular ageing is one of the main drivers of organismal ageing and holds keys towards improving the longevity and quality of the extended life. Elucidating mechanisms underlying the emergence of the aged cells as well as their altered responses to the environment will help understanding the evolutionarily defined longevity preferences across species with different strategies of survival. Much is understood about the role of alterations in the DNA, including many epigenetic modifications such as methylation, in relation to the aged cell phenotype. While transcriptomes of the aged cells are beginning to be better-characterised, their translational responses remain under active investigation. Many of the translationally controlled homeostatic pathways are centred around mitigation of DNA damage, cell stress response and regulation of the proliferative potential of the cells, and thus are critical for the aged cell function. Translation profiling-type studies have boosted the opportunities in discovering the function of protein biosynthesis control and are starting to be applied to the aged cells. Here, we provide a summary of the current knowledge about translational mechanisms considered to be commonly altered in the aged cells, including the integrated stress response-, mechanistic target of Rapamycin- and elongation factor 2 kinase-mediated pathways. We enlist and discuss findings of the recent works that use broad profiling-type approaches to investigate the age-related translational pathways. We outline the limitations of the methods and the remaining unknowns in the established ageing-associated translation mechanisms, and flag translational mechanisms with high prospective importance in ageing, for future studies.

Dynamics of mRNA fate during light stress and recovery: from transcription to stability and translation

“…During early stress, there was a slight bias towards decreased RPL, indicating translational repression of many genes. This aligns with the observations that stress initially represses translation by perturbing the machinery involved in initiation, scanning and elongation (Bresson et al, 2020;Janapala et al, 2019;Merret et al, 2015;Shalgi et al, 2013;Shirokikh & Preiss, 2018;Woodward & Shirokikh, 2021). On the contrary, we observed a striking increase in RPL during late stress that occurred independently of changes in total mRNA levels.…”

Genetic perturbation of mitochondrial function reveals functional role for specific mitonuclear genes, metabolites and pathways that regulate lifespan

“…Lifespan extension upon a decrease in overall protein biosynthesis is a phenomenon that is conserved in different model organisms [75][76][77]. Contradictorily, we found that proteins involved in ribosome biosynthesis and components of cytosolic ribosomes involved in cytosolic translation are positively correlated with RLS, indicating increased but not decreased cytosolic translation machinery in long-living mtKO strains.…”

A post-transcriptional regulatory landscape of aging in the female mouse hippocampus

“…Most prevalent was the translational repression of mRNAs coding for ribosomal proteins (RPs) in older animals (i.e., particularly prominent by comparing 20- vs. 3- or 6-month-old mice). Translational repression of RPs was previously recognised in other tissues and could thus frame a hallmark of aging ( Anisimova et al, 2020 ; Woodward and Shirokikh, 2021 ). Interestingly though, we found that the observed translational repression is preceded by a significant increase of respective mRNA levels from young adults to middle-aged animals (i.e., comparing 6 vs. 3 months).…”

“…While characterizing the genome-wide expression of transcripts has provided valuable insights into the impact of aging on cellular and molecular functions, translation substantially contributes to the regulation of protein-coding gene expression ( Sonenberg and Hinnebusch, 2009 ; Woodward and Shirokikh, 2021 ). As such, translatome analysis enables to monitor translational regulation of gene expression, solely by focusing on active transcripts associated with ribosomes ( King and Gerber, 2016 ).…”