Altered translation elongation contributes to key hallmarks of aging in killifish brain

Aging is a major risk factor for neurodegeneration and is characterized by diverse cellular and molecular hallmarks. To understand their origin, we studied the effects of aging on the transcriptome, translatome, and proteome in the brain of short-lived killifish. We identified a cascade of events in which aberrant translation pausing led to altered abundance of proteins independently of transcriptional regulation. In particular, aging caused increased ribosome stalling and widespread depletion of proteins enriched in basic amino acids. These findings uncover a potential vulnerable point in the aging brain's biology – the biogenesis of basic DNA- and RNA-binding proteins. This vulnerability may represent a unifying principle that connects various aging hallmarks, encompassing genome integrity, proteostasis and the biosynthesis of macromolecules. Overall design: Comparative analysis of transcriptome (RNA-seq) and translatome (Ribosome profiling) of Nothobranchius furzeri brain and liver from three age groups (5wph, 12wph, and 39wph). tRNA quantification of the brain from two age groups (5wph, 39wph).