Good news! Did you know that ribosome collisions are more frequent in older brains?
"These hallmarks [of aging] encompass almost all aspects of cellular physiology" What are these hallmarks are good for if they include almost anything?
Maybe the killifish is too short lived for such brain studies or how much can be transferred to human brains.
"In a new study ... researchers have discovered the cascade of events that leads to declining proteostasis in aging brains.
The findings, based on study of the turquoise killifish, lay the foundation for developing therapies that can combat and prevent neurodegenerative diseases in people – and the gradual decline in mental abilities we will all face one day. ...
Killifish, the shortest-lived vertebrates bred in captivity, develop many issues as they grow old and provide a great model of accelerated aging. ...
lab explores how cells achieve proteostasis and has previously focused on how aging affects proteostasis in the simple models of aging provided by yeast and roundworms. The new study confirms that aging processes observed in those simple organisms reflect those in more complex vertebrates like killifish – and humans. ...
Ultimately, the team located the disruption at a specific stage of protein synthesis called translation elongation. In this step, the ribosome enacts its role as the cellular machinery responsible for converting mRNA into proteins by moving along the mRNA and adding amino acids one by one. In the aging fish brains, the researchers documented ribosomes colliding and stalling, which both resulted in reduced levels of proteins and protein aggregation. ..."
From the abstract of the perspective:
"Aging is driven by several concurrent biological processes, which can be summarized in a subset of core alterations referred to as the hallmarks of aging. These hallmarks encompass almost all aspects of cellular physiology and are known to be evolutionarily well conserved.
Protein homeostasis (proteostasis) ensures that proteins are correctly made, folded, and degraded when no longer needed.
Disruption in proteostasis is a key feature of normal aging and often occurs alongside other hallmarks of aging, including genome instability, mitochondrial dysfunctions, and epigenetic alterations. Nonetheless, a definitive molecular link between impaired proteostasis and other aging hallmarks has yet to be established. On page 478 of this issue, Di Fraia et al. (3) report a comprehensive biochemical investigation of brain aging in the killifish (Nothobranchius furzeri) that identifies disrupted production of a group of essential proteins as a link between impaired proteostasis and other hallmarks of aging."
From the editor's summary and abstract:
"Editor’s summary
To get a handle on what falls apart during aging in the brain, Di Fraia et al. turned to the short-lived killifish (see the Perspective by Dionne and Laurent). The authors monitored changes in protein and RNA abundance, protein solubility, post-translational modification, and organelle composition as the fish aged.
As organisms age, protein abundance is less closely coupled to transcript abundance. In the fish, this appeared to have less to do with protein stability and was more likely influenced by altered translation. Proteins rich in basic amino acids, a characteristic of RNA and DNA binding proteins, had delays in translation and decreased in abundance. Changes in mitochondrial composition were also noted as likely contributors to loss of function in aging. ...
INTRODUCTION
Aging brains are characterized by a series of molecular and cellular changes known as aging hallmarks. Among these, a decline in protein homeostasis (proteostasis) marked by reduced clearance and increased protein damage and aggregation has received particular attention as a plausible link between brain aging and those neurodegenerative diseases also characterized by protein aggregation. A notable phenomenon in brain aging is a loss of concordance between mRNA and protein levels, whereby age-linked changes in mRNA do not necessarily lead to proportional changes in protein levels. In this study, we set out to investigate the causes of this “protein-transcript decoupling” and how impaired protein synthesis might contribute to other hallmarks of brain aging.
RATIONALE
We used the short-lived African turquoise killifish, which exhibits a naturally compressed life span and accelerated brain aging, to undertake a comprehensive investigation of age-related decline in brain proteostasis. We compared young, adult, and old killifish brains at the levels of amino acid concentrations, tRNAs, mRNAs (transcriptome), actively translated mRNAs (translatome), proteins (proteome), protein modifications [phosphorylation (Ph), ubiquitylation (Ub), and acetylation (Ac)], and protein solubility and subcellular localization. ...
RESULTS
We observed alterations in all molecular signatures investigated, ranging from amino acid concentrations to protein solubility and localization.
A clear pattern of proteostasis dysfunction emerged: Although the synthesis of some proteins was enhanced, there was a widespread reduction of proteins enriched in positively charged (basic) amino acids. Notably, many DNA and RNA binding proteins exhibited reduced abundance in old brains, decreasing at the protein but not the transcript levels.
Ribosome profiling (Ribo-seq) revealed that brain aging increased ribosome stalling. Accordingly, ribosome collisions were more frequent in old brains. Crucially, stalling events occurred disproportionately on stretches enriched in lysine and arginine codons, thus affecting translation of mRNAs encoding proteins enriched in these basic amino acids, leading to a decline in their protein levels in old brains.
Aging-affected proteins included ribosomal subunits and proteins involved in DNA repair, transcription, chromatin maintenance, and RNA splicing and export, which all mediate processes influenced by aging.
Ribosome stalling was also associated with increased protein insolubility, likely owing to nascent polypeptide misfolding. Partial proteasome inhibition affected aging hallmarks distinct from those linked to translation dysfunction and primarily influenced lysosomes and mitochondria.
CONCLUSION
This work identifies altered translation elongation and impaired protein biogenesis as hallmarks of brain aging in a short-lived vertebrate. Increased ribosome pausing is proposed as a key mechanism contributing to the mismatch between mRNA and protein changes observed in aged brains, leading to proteome aging by altering the production of proteins essential for genome integrity, mRNA transcription, splicing, protein synthesis, and mitochondrial function. This mechanism thereby links translation and proteostasis decline to other hallmarks of aging and may also be implicated in neurodegenerative diseases where similar ribosome dysfunction and protein misfolding occur."
Study involving turquoise killifish pinpoints key mechanism of brain aging
Translational traffic jam in aging brains (no public access)
Altered protein synthesis remodels the aging brain proteome.
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