Selective impairment of translation contributes to brain aging in killifish

Aging selectively impairs the production of crucial DNA- and RNA-binding proteins, which contributes to hallmarks of aging in the brains of killifish, according to a new study. The findings advance our understanding of the relationship between aging and the risk of pathologies including neurodegenerative disease. “A critical next step will be to determine whether these mechanisms are conserved in mammals, particularly in humans, where translational control is intricately linked to neurodegeneration and other age-associated diseases,” write Olivier Dionne and Benoit Laurent in a related Perspective. “This could inform the development of pharmacological strategies to modify proteostasis with the aim of delaying the onset of age-related pathologies and ultimately extending healthy years of life.”

As organisms age, their ability to maintain protein homeostasis, or proteostasis, deteriorates. Proteostasis plays a crucial role in maintaining protein quality by ensuring proper synthesis, folding, and timely degradation. Disruption to proteostasis can result in the accumulation of harmful protein aggregates, which is a hallmark of both aging and neurodegenerative diseases. Although the age-related breakdown of proteostasis often appears alongside disruptions in other hallmark processes of aging, whether proteostasis impairment actively drives these changes remains unknown.

To address this gap, Domenico Di Fraia and colleagues investigated how aging affects mRNA and protein regulation in the brain of the killifish (Nothobranchius furzeri). The killifish is a model well suited for studying aging due to its rapid life cycle and conserved aging brain hallmarks. The authors developed a method for partially inhibiting the proteasome over time to determine whether this specific impairment triggers aging-related brain changes in living animals. They used ribosome profiling (Ribo-seq) to examine how changes in mRNA translation influence protein production during aging. Di Fraia et al. discovered that as the fish aged, proteins rich in basic amino acids, such as lysine, proline, glutamine, and arginine – which are crucial for RNA- and DNA binding – decline, even though these proteins’ mRNA levels remain unchanged.

The authors linked this decline to ribosomal stalling at basic amino acid codons, which impairs translation, increases protein aggregation risk, and reduces the production of these essential proteins. The findings suggest that aging selectively impairs the synthesis of proteins essential for core gene expression and mitochondrial function, which may position proteostasis decline upstream of other aging hallmarks.