Transcriptome and Translatome Profiles of Aging in Hippocampi of Mice

The transcriptome and proteome are critical to cellular and physiological functions that change in the aging brain. The effects of aging on the subset of transcripts that are translated to proteins in the brain, i.e., the translatome, have not yet been comprehensively assessed. We quantified age-related trajectories of the hippocampal translatome and transcriptome in female C57BL/6 mice at four ages (3-, 6-, 12-, 20-month-old). We performed RNA sequencing on total RNA and polysome preparations. Aging trajectories in transcript abundance were dominated by changes in transcripts contributing to immune system processes and neuroinflammation, both of which are implicated in the development of neurodegenerative diseases. Translational efficiency analysis using AnotaSeq2 revealed dissociations between the age trajectories of the transcriptome and translatome. The discordant sets included genes encoding ribonucleoproteins, as well as genes enriched for calcium signalling implicated in age-related deficits in hippocampal-dependent behaviour. We also identified distinct alternatively spliced forms in the transcriptome and the translatome. The various alternative splicing event types were associated with distinct gene sets, that included genes enriched at synapses and dendritic compartments, as well as RNA-binding proteins. Alterations in microexons across the age groups were also observed, in particular for genes associated with neuronal processes. Finally, only minor changes were observed with aging in alternative polyadenylation selection, although a bias towards distal sites was observed for a subset of genes in the translatome. Overall, the data imply that divergence of transcriptional and translational control is key to understanding aging in the mouse hippocampus.