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 life span. We showed that the transcriptome changes govern those 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 twofold or even more. Moreover, with age, ribosome coverage gradually decreased in the vicinity of start codons and increased near stop codons, revealing complex age-related changes in the translation process. Taken together, our results reveal systematic and multidimensional deregulation of protein synthesis, showing how this major cellular process declines with age.
Highlights
Aging is associated with a gradual decline of organismal function and fitness, which in turn is tightly linked with changes in the proteome
These findings reveal systematic, multilevel deregulation in gene expression and protein synthesis, showing how this major cellular process declines with age
Principal-component analysis (PCA) has shown that 61% of variance can be explained by the first three principal components (PCs): PC1 and PC2 attributed to the sequenced tissue and PC3 to the type of experiment (Ribo- or RNA-seq)
Summary
Aging is associated with a gradual decline of organismal function and fitness, which in turn is tightly linked with changes in the proteome. Disruption of proteostasis is a well-known cause of aging-associated diseases This age-related dysfunction is believed to influence organisms in a systemic and chronic way, decreasing their stress resistance and the ability to clear misfolded proteins [1]. Most of the interventions known to extend life span are associated with suppression of metabolism (e.g., caloric restriction) or inhibition of nutrient signaling (e.g., rapamycin), regulating protein synthesis and biosynthesis of translation machinery components [19]. Ribosomes were depleted in the vicinity of start codons and increased near stop codons These findings reveal systematic, multilevel deregulation in gene expression and protein synthesis, showing how this major cellular process declines with age.
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