Multi-faceted deregulation of gene expression and protein synthesis with age

Abstract

Protein synthesis represents a major metabolic activity of the cell. However, how it is affected by aging and how this in turn impacts cell function remains largely unexplored. To address this question, herein we characterized age-related changes in both the transcriptome and translatome of mouse tissues over the entire lifespan. Expression of the majority of differentially expressed genes followed a U-shaped curve with the turning point around 3-months-old. We showed that transcriptome changes govern changes in the translatome and are associated with altered expression of genes involved in inflammation, extracellular matrix and lipid metabolism. We also identified genes that may serve as candidate biomarkers of aging. At the translational level, we uncovered sustained down-regulation of a set of 5' terminal oligopyrimidine (5'TOP) transcripts encoding protein synthesis and ribosome biogenesis machinery and regulated by the mTOR pathway. For many of them, ribosome occupancy dropped 3-fold or even more. Moreover, with age, ribosome coverage gradually decreased in the vicinity of start codons and increased near stop codons, revealing complex agerelated changes in the translation process. Taken together, our results reveal systematic and multidimensional deregulation in protein synthesis, showing how this major cellular process declines with age.

Evolutionary transcriptomics reveals longevity mostly driven by polygenic and indirect selection in mammals

“…For example, naked mole-rat has higher translational fidelity than mouse (74). Transfer RNA aminoacylation is inhibited in senescent cells to limit protein synthesis errors (75). In addition, seryl-tRNA can directly bind to telomere repeat sequences, leading to telomere shortening and cell senescence (76).…”

Integration of differential gene expression with weighted gene correlation network analysis identifies genes whose expression is remodeled throughout physiological aging in mouse tissues

“…The most commonly reported age-related dysregulations involve the immune system [9,11–13] where inflammatory response genes are upregulated even in the absence of pathogen infection [5,6,9,11,14–19]. Energy metabolism, redox homeostasis, and mitochondrial function alterations are also frequently observed in age- related studies [6,9,11,15–18,20], particularly the downregulation of genes encoding mitochondrial ribosomal proteins and components of the electron transport chain [5,11,14–16,18], protein synthesis machinery [5,11,17], developmental and cell differentiation genes [9,11,19], and extracellular matrix components [6,14–16]. Up-regulated genes are associated with the stress response and DNA repair [5,6,9,11,14,16–18], RNA processing [11,12,17] and cell cycle arrest [5,16,21].…”

“…Energy metabolism, redox homeostasis, and mitochondrial function alterations are also frequently observed in age- related studies [6,9,11,15–18,20], particularly the downregulation of genes encoding mitochondrial ribosomal proteins and components of the electron transport chain [5,11,14–16,18], protein synthesis machinery [5,11,17], developmental and cell differentiation genes [9,11,19], and extracellular matrix components [6,14–16]. Up-regulated genes are associated with the stress response and DNA repair [5,6,9,11,14,16–18], RNA processing [11,12,17] and cell cycle arrest [5,16,21]. Despite this, the existence of specific genetic signatures of aging continue to be a matter of debate as gene regulation is mostly tissue-specific [5–7,15,20,22–25], but also because there is focus on comparisons between young and old individuals without much consideration of the dynamics of gene expression throughout the lifespan.…”