A groundbreaking study published in Science illuminates the intricate molecular mechanisms by which aging disrupts protein synthesis in the brain, shedding light on a fundamental process that may underlie the development of age-associated neurodegenerative diseases. By focusing on the short-lived killifish (Nothobranchius furzeri), a powerful vertebrate model organism renowned for its rapid aging and conservation of key hallmarks of brain aging, researchers have uncovered how the fidelity of mRNA translation deteriorates with age, leading to selective impairments in the production of critical DNA- and RNA-binding proteins. This discovery offers profound insights into the delicate balance of proteostasis—the maintenance of protein homeostasis—and how its breakdown potentially drives neuronal dysfunction and degeneration.
Proteostasis is integral to cellular health, governing the synthesis, folding, modification, and degradation of proteins to ensure the cellular proteome remains functional and adaptable to physiological demands. The disruption of proteostasis is a recognized hallmark of aging and is implicated in a spectrum of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases, which share a common feature of harmful protein aggregation. Despite extensive research, the exact molecular events linking aging to the collapse of proteostasis and the consequent pathological cascades remain elusive. The current study, led by Domenico Di Fraia and colleagues, advances this understanding by systematically mapping alterations in translational control as organisms age.
Utilizing ribosome profiling (Ribo-seq), an innovative technique that captures snapshots of actively translating ribosomes on mRNA transcripts, the researchers precisely quantified how the translation landscape changes within the brains of killifish as they transition from youth to senescence. Intriguingly, although the overall abundance of messenger RNA transcripts coding for essential DNA- and RNA-binding proteins remained stable, the translation efficiency of these transcripts markedly declined with age. This uncoupling between mRNA levels and protein synthesis implies a post-transcriptional regulatory deficit emerging during aging, specifically affecting translation elongation dynamics.
Delving deeper, the study identified that proteins rich in basic amino acids—namely lysine, proline, glutamine, and arginine—are disproportionately affected during aging. These amino acids, positively charged under physiological conditions, are critical components of proteins involved in nucleic acid binding and chromatin modulation, processes central to gene expression regulation and mitochondrial function. The translational machinery encounters ribosomal stalling precisely at codons encoding these amino acids, thereby impeding smooth peptide elongation and ultimately resulting in the diminished production of these fundamental proteins.
Ribosomal stalling is a phenomenon whereby the ribosome halts prematurely during the elongation phase of translation, often triggering quality control mechanisms to address aberrant proteins. Persistent stalling, as observed in aged killifish brains, can lead to increased vulnerability to proteotoxic stress, as stalled ribosomes and incomplete polypeptides create a substrate for aggregation. These aggregates exacerbate cellular stress and can initiate neurotoxic pathways, reinforcing the notion that proteostasis decline is not merely a downstream consequence but may actively drive the decline in neuronal integrity seen during aging.
To interrogate causality, the team implemented a method to partially inhibit proteasome function in vivo over time, mimicking the age-associated decline in protein degradation capacity. This intervention accelerated the appearance of aging-like phenotypes in the brain, including alterations consistent with those observed naturally during killifish aging. These results robustly connect impaired proteasomal activity and translational dysregulation as intertwined processes that deteriorate proteostasis, precipitating the accumulation of defective proteins and dysfunctional cellular states.
Strikingly, the decline in the production of these basic amino acid–rich proteins suggests that age-related translational impairments are selective, targeting core components essential for maintaining genomic stability and mitochondrial efficiency. Given that mitochondrial dysfunction and genomic instability are themselves hallmarks of aging, these findings position altered translation elongation as a potentially upstream driver orchestrating a cascade of molecular setbacks culminating in organismal aging.
The study’s implications transcend the killifish model; they beckon a reevaluation of translational control mechanisms in mammalian and human aging. As Olivier Dionne and Benoit Laurent highlight in a complementary Perspective, deciphering whether such translation elongation impairments are conserved in humans carries profound biomedical significance. The tight link between translational fidelity and neurodegenerative disease etiology posits that pharmacological modulation of translational machinery may emerge as a promising therapeutic avenue to restore proteostasis and delay the onset of neurodegenerative pathologies.
Moreover, the nuanced understanding of ribosomal stalling at specific codon sequences introduces new perspectives on codon usage bias and its impact on age-related diseases. Future research may leverage this knowledge to engineer targeted interventions that alleviate ribosomal pausing or enhance ribosome recycling efficiency, thereby preserving protein synthesis integrity during aging.
In essence, this research elevates the significance of translation elongation as a pivotal node in the complex network of aging biology, providing a platform for developing novel strategies aimed at extending healthy lifespan by sustaining proteome quality. The killifish model, with its rapid aging trajectory, has proven invaluable in unveiling these molecular vulnerabilities, offering a powerful tool for accelerated aging research and drug discovery.
This comprehensive exploration of age-driven translational impairment enriches the broader aging research field and underscores the intricate molecular choreography underpinning life’s decline. Ultimately, interventions targeting the restoration of translation elongation dynamics hold the promise of mitigating age-associated cognitive decline, neurodegeneration, and perhaps even systemic aging, heralding a new era of precision gerontology.
Subject of Research: Aging-related impairments in protein translation and proteostasis in the killifish brain
Article Title: Altered translation elongation contributes to key hallmarks of aging in killifish brain
News Publication Date: 31-Jul-2025
Web References: http://dx.doi.org/10.1126/science.adk3079
References: Di Fraia et al., Science, DOI: 10.1126/science.adk3079 (2025)
Image Credits: Not specified
Keywords: Aging, proteostasis, translation elongation, ribosomal stalling, killifish, neurodegeneration, protein synthesis, DNA-binding proteins, RNA-binding proteins, ribosome profiling, mitochondria, protein aggregation
