Transfer RNAs (tRNAs) are key players of protein synthesis, as they decode the genetic information organized in mRNA codons, translating them into the code of 20 amino acids. To be fully active, tRNAs undergo extensive post-transcriptional modifications, catalyzed by different tRNA-modifying enzymes. Lack of these modifications increases the level of missense errors and affects codon decoding rate, contributing to protein aggregation with deleterious consequences to the cell. Recent works show that tRNA hypomodification and tRNA-modifying-enzyme deregulation occur in several diseases where proteostasis is affected, namely, neurodegenerative and metabolic diseases. In this review, we discuss the recent findings that correlate aberrant tRNA modification with proteostasis imbalances, in particular in neurological and metabolic disorders, and highlight the association between tRNAs, their modifying enzymes, translational decoding, and disease onset.

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Gene expression alterations occurring with aging have been described for a multitude of species, organs, and cell types. However, most of the underlying studies rely on static comparisons of mean gene expression levels between age groups and do not account for the dynamics of gene expression throughout the lifespan. These studies also tend to disregard the pairwise relationships between gene expression profiles, which may underlie commonly altered pathways and regulatory mechanisms with age. To overcome these limitations, we have combined segmented regression analysis with weighted gene correlation network analysis (WGCNA) to identify high-confidence signatures of aging in the brain, heart, liver, skeletal muscle, and pancreas of C57BL/6 mice in a publicly available RNA-Seq dataset (GSE132040). Functional enrichment analysis of the overlap of genes identified in both approaches showed that immune- and inflammation-related responses are prominently altered in the brain and the liver, while in the heart and the muscle, aging affects amino and fatty acid metabolism, and tissue regeneration, respectively, which reflects an age-related global loss of tissue function. We also explored sexual dimorphism in the aging mouse transcriptome and found the liver and the muscle to have the most pronounced gender differences in gene expression throughout the lifespan, particularly in proteostasis-related pathways. While the data showed little overlap among the age-dysregulated genes between tissues, aging triggered common biological processes in distinct tissues, which we highlight as important features of murine tissue physiological aging.

Aging can be defined as the progressive deterioration of cellular, tissue, and organismal function over time. Alterations in protein homeostasis, also known as proteostasis, are a hallmark of aging that lead to proteome imbalances and protein aggregation, phenomena that also occur in age-related diseases. Among the various proteostasis regulators, microRNAs (miRNAs) have been reported to play important roles in the post-transcriptional control of genes involved in maintaining proteostasis during the lifespan in several organismal tissues. In this review, we consolidate recently published reports that demonstrate how miRNAs regulate fundamental proteostasis-related processes relevant to tissue aging, with emphasis on the two most studied tissues, brain tissue and skeletal muscle. We also explore an emerging perspective on the role of miRNA regulatory networks in age-related protein aggregation, a known hallmark of aging and age-related diseases, to elucidate potential miRNA candidates for anti-aging diagnostic and therapeutic targets.

Gene expression alterations occur in all mouse tissues during aging, but recent works highlight minor rather than major dysregulation amplitude for most genes, questioning whether differentially expressed genes on their own provide deep insight into aging biology. To clarify this issue, we have combined differential gene expression with weighted gene correlation network analysis (WGCNA) to identify expression signatures accounting for the pairwise relations between gene expression profiles and the cumulative effect of genes with small fold-changes during aging in the brain, heart, liver, skeletal muscle, and pancreas of C57BL/6 mice. Functional enrichment analysis of the overlap of genes identified in both approaches showed that immunity-related responses, mitochondrial energy metabolism, tissue regeneration and detoxification are prominently altered in the brain, heart, muscle, and liver, respectively, reflecting an age-related global loss of tissue function. While data showed little overlap among the age-dysregulated genes between tissues, aging triggered common biological processes in distinct tissues, particularly proteostasis-related pathways, which we highlight as important features of murine tissue physiological aging.