Ribosome Molecular Aging Shapes Translation Dynamics
Posted on: 1 June 2026
Preprint posted on 9 March 2026
In old age, virtually all biological processes begin to decline. This preprint delves into how ribosomes – the microscopic 3D printers that synthesize our proteins – change across their lifetimes and start to fail.
Selected by Scott Murray Cors
Categories: cell biology, genetics, molecular biology
Background
In every one of our cells, new proteins are constantly being synthesized. This process is carried out by ribosomes, which translate mRNA into proteins. Interestingly, ribosomal subunits can persist for several weeks, far exceeding the turnover rates of most cellular proteins. This longevity raises an important question: does ribosome function decline over time?
In the preprint highlighted here, the authors tracked and isolated aged ribosomes using a new labelling strategy in human osteosarcoma (U2OS) cells. This approach involves fusing a HaloTag to either RPL10A or RPS17 to label the large (60S) or small (40S) ribosomal subunits, respectively. By treating the cells with a fluorescent TMR ligand (which irreversibly binds the HaloTag), the 40S or 60S subunit can be tracked over time.
This HaloTag-TMR labelling strategy for these cells can be modified to selectively track pre-existing (label-block) or newly synthesized (block-label) ribosomes (Fig. 1).
Fig. 1 HaloTag-TMR labelling strategies for U2OS cells. Note that for simplicity, I only show labelling of the 60S subunit, but this is likewise done for the 40S subunit. Made in Biorender (student membership).
Main findings
Use the summary mind map below to follow along this section (Fig 2.).
Fig 2. Selection of ribosome ageing hallmarks shown by the paper. Note that all results shown here exclusively come from pre-existing ribosomes that were labelled. Made in Biorender (student membership).
- Old ribosomes are less likely to organize into polysomes
Ribosomes can translate mRNA either individually as monosomes or collectively as polysomes, where multiple ribosomes latch on to the same transcript. To determine whether aged ribosomes exist as monosomes or polysomes, the researchers selectively labelled pre-existing 40S or 60S subunits and tracked them for 72 hours. Cell lysates were separated using sucrose gradient centrifugation, which resolves ribosomal subunits, monosomes, and polysomes by their densities. The researchers then isolated each fraction and performed western blotting against the TMR ligand to isolate aged ribosomes. Remarkably, they found that these aged ribosomes preferentially existed as monosomes versus polysomes, showing an overall depletion of polysomes.
- Old ribosomes translate different types of mRNA at different rates
To see which specific mRNAs are differentially translated in aged ribosomes, the researchers performed ribosome profiling (Ribo-seq). This technique involves lysing cells and treating them with RNase I to digest any mRNA regions unprotected by the ribosome, leaving behind so-called footprints that represent actively translating mRNA regions. By sequencing these fragments, the researchers calculated translation efficiency, defined as the ratio of ribosome-protected fragment abundance to total mRNA abundance.
What they found was particularly striking: mRNAs enriched in codons for hydrophobic amino acids showed increased translation efficiency in aged ribosomes compared to steady-state conditions (all ribosomes), while mRNAs enriched in codons for basic amino acids showed reduced translation. These trends were consistent across both the 40S and 60S subunits.
- Old ribosomes tend to stall and collide with each other during translation
From there, the researchers dug deeper into the downregulated mRNAs and investigated why they have a lower translation efficiency. Looking at the ribosome-protected codons along the transcript, they found a striking pattern: ribosome occupancy was abnormally high just after the start codon, but then sharply declined further along the transcript. It was as if the ribosomes suddenly paused at the beginning, then fell off the transcript, effectively causing premature translation termination. What the researchers found was that these sites were enriched in codons for basic amino acids, suggesting that – for some reason – aged ribosomes really struggle to translate these regions.
In an additional experiment, the researchers lysed the cells and added RNAase to dissociate ribosomes tethered together by the same transcript. Surprisingly, even after RNAase treatment, aged ribosomes were more likely to be stuck together as disomes – indicating that they are more likely to collide with each other.
- Old ribosomes have a reduction in 18S rRNA 210-pseudouridylation
The next question you might be wondering is: why is translation efficiency reduced for transcripts enriched in codons for basic amino acids? The researchers hypothesized that the culprits – collided ribosomes – may have aberrant rRNA modifications. To investigate this, they isolated the disome fraction and pulled down aged 60S subunits. They then used a recently developed technique called BID-seq to profile the associated 40S ribosome for a specific rRNA modification called pseudouridylation (Ψ). Here, they found a selective depletion of 18S rRNA 210-pseudouridylation (Ψ18S-210) in the 40S subunit.
To determine if the depletion of this rRNA modification is a causative factor, they overexpressed an enzyme that catalyzes the conversion of uridine to pseudouridine (SNORA10) to increase overall Ψ18S-210 levels. Remarkably, this reduced the number of collided ribosomes (disomes) and improved the translation efficiency of polybasic lysine (AAA) transcripts, suggesting that Ψ18S-210 depletion drives stalling at codons for basic amino acids.
- There are fewer translating ribosomes in aged worms
The researchers next asked whether they could track aging ribosomes in vivo using C. elegans. To do this, they fused a HaloTag to Rpl10a, allowing them to label and track the 60S subunit using a fluorescent TMR ligand. They incubated 1-day-old worms with the TMR ligand for 24 hours, followed by an extensive washout for an additional 8 days. On Day 10, the nematodes were homogenized, and the lysate was treated with a nuclease to collapse actively translating polysomes into 80S monosomes. This allowed the researchers to calculate the ratio of translating 80S ribosomes to free 60S subunits.
The major finding here was that the ratio of 80S to 60S ribosomes was significantly lower in 10-day-old worms, indicating an overall reduction in translation activity.
What I like about this preprint
Tracking aged ribosome populations in this way allows the researchers to look at the intrinsic mechanisms of ribosome ageing without the confound of an aged environment. This makes it highly complementary to research on aged organisms. On a deeper note, I believe that understanding how each individual component of cell biology declines during aging will help us piece together a comprehensive map of cellular aging. This way, we can tackle many age-related diseases through a conserved set of mechanisms. In other words, we can kill dozens of birds with one stone!
Minor suggestions
- Perhaps there is a small chance that RPL10A and RPS17 naturally swap out of the ribosome, potentially depleting the TMR signal too early?
- Maybe try depleting Ψ18S-210 levels in younger ribosomes to see if that recapitulates the stalling phenotypes of aged ribosomes?
Questions for authors
- How viable is this labelling strategy for larger organisms such as rodents?
- Could this labelling strategy be applied to the aging proteasome?
- Could overexpressing SNORA10 extend the lifespan of C. elegans?
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Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
| List by | Maiko Kitaoka et al. |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
| List by | Sandra Malmgren Hill |
Zebrafish immunology
A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.
| List by | Shikha Nayar |
Also in the molecular biology category:
preLighters’ choice – Handpicked DevBio preprints
preLighters with expertise across developmental and stem cell biology have nominated a few developmental biology (and related) preprints they’re excited about and explain in a few paragraph why. Concise preprint highlights, prepared by the preLighter community – a quick way to spot upcoming trends, new methods and fresh ideas.
| List by | Theodora Stougiannou et al. |
BSDB Spring Meeting: Molecules to Morphogenesis
The British Society for Developmental Biology (BSDB) Spring Meeting Molecules to Morphogenesis was held from 23–26 March 2026 at the University of Warwick (UK). This meeting brought together a vibrant community of researchers to discuss how molecular mechanisms are integrated across scales to drive morphogenesis, spanning diverse model systems and approaches. This preList contains preprints by presenters from the talk and poster sessions at the meeting. Please do get in touch at preLights@biologists.com if you notice any relevant preprints that we may have missed.
| List by | Ingrid Tsang |
Keystone Symposium on Stem Cell Models in Embryology 2026
The Keystone Symposium on Stem Cell Models in Embryology, 2026, was organised by Jun Wu (UT Southwestern), Jianping Fu (University of Michigan) and Miki Ebisuya (TU Dresden) and held at Asilomar Conference Grounds in California (US). The meeting discussed recent advances made in establishing stem-cell-based embryo models, what fundamental insights into developmental processes have been gleaned from them, as well as how they are beginning to be applied more widely. This prelist contains preprints by presenters at the talk and poster sessions at the conference, which our Reviews Editor in attendance spotted. Please do reach out to preLights@biologists.com if you notice any that we’ve missed.
| List by | Ingrid Tsang |
SciELO preprints – From 2025 onwards
SciELO has become a cornerstone of open, multilingual scholarly communication across Latin America. Its preprint server, SciELO preprints, is expanding the global reach of preprinted research from the region (for more information, see our interview with Carolina Tanigushi). This preList brings together biological, English language SciELO preprints to help readers discover emerging work from the Global South. By highlighting these preprints in one place, we aim to support visibility, encourage early feedback, and showcase the vibrant research communities contributing to SciELO’s open science ecosystem.
| List by | Carolina Tanigushi |
October in preprints – DevBio & Stem cell biology
Each month, preLighters with expertise across developmental and stem cell biology nominate a few recent developmental and stem cell biology (and related) preprints they’re excited about and explain in a single paragraph why. Short, snappy picks from working scientists — a quick way to spot fresh ideas, bold methods and papers worth reading in full. These preprints can all be found in the October preprint list published on the Node.
| List by | Deevitha Balasubramanian et al. |
October in preprints – Cell biology edition
Different preLighters, with expertise across cell biology, have worked together to create this preprint reading list for researchers with an interest in cell biology. This month, most picks fall under (1) Cell organelles and organisation, followed by (2) Mechanosignaling and mechanotransduction, (3) Cell cycle and division and (4) Cell migration
| List by | Matthew Davies et al. |
September in preprints – Cell biology edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading list. This month, categories include: (1) Cell organelles and organisation, (2) Cell signalling and mechanosensing, (3) Cell metabolism, (4) Cell cycle and division, (5) Cell migration
| List by | Sristilekha Nath et al. |
June in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: (1) Cell organelles and organisation (2) Cell signaling and mechanosensation (3) Genetics/gene expression (4) Biochemistry (5) Cytoskeleton
| List by | Barbora Knotkova et al. |
May in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) Biochemistry/metabolism 2) Cancer cell Biology 3) Cell adhesion, migration and cytoskeleton 4) Cell organelles and organisation 5) Cell signalling and 6) Genetics
| List by | Barbora Knotkova et al. |
Keystone Symposium – Metabolic and Nutritional Control of Development and Cell Fate
This preList contains preprints discussed during the Metabolic and Nutritional Control of Development and Cell Fate Keystone Symposia. This conference was organized by Lydia Finley and Ralph J. DeBerardinis and held in the Wylie Center and Tupper Manor at Endicott College, Beverly, MA, United States from May 7th to 9th 2025. This meeting marked the first in-person gathering of leading researchers exploring how metabolism influences development, including processes like cell fate, tissue patterning, and organ function, through nutrient availability and metabolic regulation. By integrating modern metabolic tools with genetic and epidemiological insights across model organisms, this event highlighted key mechanisms and identified open questions to advance the emerging field of developmental metabolism.
| List by | Virginia Savy, Martin Estermann |
April in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry/metabolism 2) cell cycle and division 3) cell organelles and organisation 4) cell signalling and mechanosensing 5) (epi)genetics
| List by | Vibha SINGH et al. |
Biologists @ 100 conference preList
This preList aims to capture all preprints being discussed at the Biologists @100 conference in Liverpool, UK, either as part of the poster sessions or the (flash/short/full-length) talks.
| List by | Reinier Prosee, Jonathan Townson |
February in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry and cell metabolism 2) cell organelles and organisation 3) cell signalling, migration and mechanosensing
| List by | Barbora Knotkova et al. |
Community-driven preList – Immunology
In this community-driven preList, a group of preLighters, with expertise in different areas of immunology have worked together to create this preprint reading list.
| List by | Felipe Del Valle Batalla et al. |
January in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry/metabolism 2) cell migration 3) cell organelles and organisation 4) cell signalling and mechanosensing 5) genetics/gene expression
| List by | Barbora Knotkova et al. |
2024 Hypothalamus GRC
This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.
| List by | Nathalie Krauth |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
| List by | Rob Hynds |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
| List by | Sandra Franco Iborra |