Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Dec;25(12):5265-5276.
doi: 10.1038/s44319-024-00315-2. Epub 2024 Nov 19.

Regulating translation in aging: from global to gene-specific mechanisms

Mathilde Solyga  1 , Amitabha Majumdar  2 , Florence Besse  3
Affiliations
Review

Regulating translation in aging: from global to gene-specific mechanisms

Mathilde Solyga et al. EMBO Rep. 2024 Dec.

Abstract

Aging is characterized by a decline in various biological functions that is associated with changes in gene expression programs. Recent transcriptome-wide integrative studies in diverse organisms and tissues have revealed a gradual uncoupling between RNA and protein levels with aging, which highlights the importance of post-transcriptional regulatory processes. Here, we provide an overview of multi-omics analyses that show the progressive uncorrelation of transcriptomes and proteomes during the course of healthy aging. We then describe the molecular changes leading to global downregulation of protein synthesis with age and review recent work dissecting the mechanisms involved in gene-specific translational regulation in complementary model organisms. These mechanisms include the recognition of regulated mRNAs by trans-acting factors such as miRNA and RNA-binding proteins, the condensation of mRNAs into repressive cytoplasmic RNP granules, and the pausing of ribosomes at specific residues. Lastly, we mention future challenges of this emerging field, possible buffering functions as well as potential links with disease.

Keywords: Aging; Post-transcriptional Regulation; RNA; RNA-Binding Proteins; Tanslation.

PubMed Disclaimer

Conflict of interest statement

Disclosure and competing interests statement. The authors declare no competing interests.

Figures

Figure 1
Figure 1. Overview of post-transcriptional regulatory mechanisms.
Once exported from the nucleus to the cytoplasm, mRNAs undergo post-transcriptional regulation at three different levels: stability, localization, and translation. These processes, represented in the inner circle, are modulated by trans-acting factors such as RNA-Binding Proteins (RBPs) or miRNAs, but also by epigenetic processes such as methylation or condensation into so-called ribonucleoproteic (RNP) granules (outer circle). RBPs regulate mRNA fate at different levels: translation, localization and stability. RBPs can have an opposite impact on translation by either promoting the recruitment of the translation machinery or preventing it through competition with translation initiation factors. Similarly, RBPs play a dual role on mRNA stability: they can protect mRNAs through capping and polyadenylation modulation or induce their cleavage and decay. Lastly, RBPs can recruit molecular motors to promote mRNA transport and remote translation. miRNAs hybridize to target mRNAs via complementary base pairing, leading to the recruitment of the RNA-induced silencing complex (RISC). This interaction can result in either translational repression or mRNA degradation. Methylation modifies the structure of RNA molecules and their binding affinity for RBPs, which can impact their stability or localization. RNP granules mediate the clustering of mRNA subsets into RBP-rich condensates that are depleted of the translation machinery and can be transported over long distances.
Figure 2
Figure 2. Age-dependent alterations in the efficiency of the translation machinery.
Schematic representation of the three main steps of elongation (left panel) and their alteration in aged individuals (right panel). During the initiation phase, the pre-initiation complex containing the small ribosomal subunit 40S scans the mRNA 5′ untranslated region (UTR) to find the start codon AUG. At this position, the large ribosomal subunit 60S is recruited to form a competent 80S ribosome. The loss of ribosomal protein stoichiometry observed with aging leads to a decreased initiation rate and a reduced number of 80S ribosome per transcript. During the elongation step, the polypeptide chain is synthesized through ribosome-mediated incorporation of amino acids via aminoacyl-tRNA codon recognition. In aged individuals, the rate of elongation, which reflects the processivity of the ribosome along the coding sequence, is decreased, thereby increasing the frequency of collisions. At the end of the coding sequence, the stop codon triggers the termination of translation and the dissociation of the ribosome from the mRNA. An increased frequency of STOP codon readthrough is observed in aging cells, inducing a partial relocalization of ribosomes to the 3’ UTR.
Figure 3
Figure 3. Trans-acting factors contributing to translational repression with aging.
Age-dependent increase in the level of trans-acting factors such as miRNA or RBPs (upper and middle parts, respectively) were shown to induce the translational repression of their target mRNAs. Condensation of RBPs and their associated mRNAs into bigger granules devoid of ribosomes (lower part) can induce their translational repression.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Adekunle DA, Hubstenberger A (2020) The multiscale and multiphase organization of the transcriptome. Emerg Top Life Sci 4:265–280 - PubMed
    1. Alberti S, Hyman AA (2021) Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing. Nat Rev Mol Cell Biol 22:196–213 - PubMed
    1. An H, de Meritens CR, Shelkovnikova TA (2021) Connecting the “dots”: RNP granule network in health and disease. Biochim Biophys Acta Mol Cell Res 1868:119058 - PubMed
    1. Anisimova AS, Alexandrov AI, Makarova NE, Gladyshev VN, Dmitriev SE (2018) Protein synthesis and quality control in aging. Aging 10:4269–4288 - PMC - PubMed
    1. Anisimova AS, Meerson MB, Gerashchenko MV, Kulakovskiy IV, Dmitriev SE, Gladyshev VN (2020) Multifaceted deregulation of gene expression and protein synthesis with age. Proc Natl Acad Sci USA 117:15581–15590 - PMC - PubMed

LinkOut - more resources