Post-transcriptional characterization of the vertebrate aging brain sheds light on the origin of protein-transcript decoupling

Aging is associated with impaired proteostasis and reduced correlation between protein and mRNA levels. The mechanisms underlying such age-dependent alterations remain unclear. Here, we used the short-lived killifish Nothobranchius furzeri to define how aging affects the transcriptome, translatome and proteome of the vertebrate brain. Integrating these analyses with protein subcellular localization, solubility, and posttranslational modifications data we uncover that basic proteins, including ribosomal and RNA-binding proteins, progressively decrease with age. In contrast, abundant and long-lived proteins, including components of the mitochondrial respiratory chain, increase or remain stable despite a decrease in their mRNA levels. Chronic proteasome inhibition can induce some aging signatures in vivo, but it does not recapitulate the age-related protein-transcript decoupling. Instead, we find increased ribosome pausing in the aging brain reprograms the translation landscape accounting for age-dependent proteome alterations independent of transcription. These changes in protein biogenesis likely reduce availability of key protein complexes in older brains. Overall design: Comparative analysis of transcriptome (RNA-seq) of Nothobranchius furzeri brain after in-vivo proteasome inhibition