Spatiotemporal transcriptomic characteristics of immune and metabolic dysregulation during mouse brain aging.

BACKGROUND: Aging and its associated neurodegenerative diseases were increasingly recognized as one of the greatest global health threats. Brain aging involved a multitude of pathological changes, including immune inflammation and metabolic dysregulation. METHODS: We systematically characterized spatiotemporal heterogeneity and dynamic gene expression profiles related to immune and metabolic dysfunction during mouse brain aging. By analyzing differentially expressed genes and conducting functional enrichment and gene set enrichment analysis, we constructed a spatiotemporal transcriptomic atlas of aging-associated metabolic and immune features. We further performed transcription factor enrichment analysis, regulatory network construction, weighted gene co-expression network analysis, and single-cell deconvolution analysis to further reveal underlying mechanisms. RESULTS: Our results showed that, throughout aging, most brain regions underwent widespread immune-inflammatory activation with distinct timing and magnitude: svz exhibited the strongest activation at 26 months, th peaks at 21 months, while olf maintained low immune activation. In terms of metabolic function, different regions responded oppositely to oxidative stress and compensatory mechanisms: mPTP pathway's genes were significantly upregulated in th but downregulated in cor. Moreover, each brain region possessed its own unique regulatory network, and the H3K27-methyltransferase activity of the PRC2 complex displayed region-dependent age dynamics, suggesting these epigenetic differences (especially ent and olf) might serve as novel targets for anti-aging interventions. CONCLUSIONS: This work presented a high-resolution spatiotemporal transcriptomic atlas of mouse brain aging, revealed regionally staggered immune activation, contrasted metabolic adaptations, and illustrated PRC2-mediated epigenetic remodeling during brain aging. These insights advanced our understanding of brain aging mechanisms and identified region-specific therapeutic targets for precision interventions in neurodegenerative diseases.