Spatiotemporal Mouse Brain Profiling Reveals Anti-Aging Mechanisms of Caloric Restriction

Aging induces functional declines in the mammalian brain, increasing its vulnerability to cognitive impairments and neurodegenerative disorders. Among various interventions to slow aging and delay age-related diseases, caloric restriction (CR) consistently extends lifespan across species. However, the specific molecular and cellular mechanisms through which CR benefits the aging brain remain unclear. In this study, we performed spatiotemporal profiling of mouse brains to uncover detailed mechanisms underlying the anti-aging effects of CR. We analyzed the transcriptional states of over half million single cells from mouse brain samples across various ages and in response to CR treatment. Monitoring the dynamics of over 300 transcriptionally distinct cellular states, we captured the temporal dynamics of cellular states particularly vulnerable to aging and those rescued by CR (e.g., CR delays the expansion of inflammatory glia and preserves neurogenesis cells). Further spatial transcriptome analysis revealed gene expression and cellular dynamics across brain regions in aged mice upon CR treatment, uncovering region-specific anti-aging effects. In summary, our spatiotemporal mouse brain profiling delineated highly cell-type-specific molecular pathways in response to aging and CR, shedding light on the nuanced regulatory roles of CR across different cell types and brain regions. Single nucleus RNA-seq profiling for caloric restricted and ad libitum C57BL/6 mouse brain cells at 12,18,24 months. Spatial transcriptomic profiling for caloric restricted and ad libitum C57BL/6 mouse brain cells at 24 months.