Sex-specific gene and isoform expression characterizes hippocampal aging in rhesus macaques

Aging induces widespread changes in gene and isoform expression within the hippocampus of rhesus macaques, yet the significance of these isoform-specific alterations remains unclear. Declining splicing fidelity, such as increased intron retention and aberrant isoform expression, may contribute to cellular dysfunction. The study employed short- and long-read RNA sequencing to analyze gene and isoform-level variations across the aging brain in 24 rhesus macaques, revealing 594 age-associated differential isoform expression events.

Both shared and sex-specific modifications were identified. Inflammatory pathways, including TNF-α- NF-κB signaling, interferon responses, and complement pathways, were enriched in both sexes. Weighted gene co-expression network analysis (WGCNA) uncovered sex-specific modules related to inflammatory, glial, mitochondrial, and hormone-responsive processes.

Intriguingly, some age-associated changes were detected at the isoform level, even when there were minimal or no differences at the gene level, indicating that transcript-level regulation could be an underexplored aspect of brain aging. To explore the relationship between aging and Alzheimer's disease (AD), the researchers conducted WGCNA analyses on both the macaque cohort and a human hippocampal AD single-nucleus RNA-sequencing dataset.

Cross-species module preservation and gene overlap analyses uncovered shared genes between age-associated and AD-associated networks, with pathway enrichment pointing to glial function, inflammation, and mitochondrial biology. Overall, these results highlight sex-specific differences in hippocampal transcriptomic aging, emphasize the importance of isoform-level regulation, and identify overlapping transcriptional signatures between normal aging and AD-related pathways.