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.

衰老会引发哺乳动物大脑的功能衰退，提升其罹患认知障碍与神经退行性疾病的易感性。在诸多延缓衰老、推迟年龄相关性疾病的干预手段中，热量限制（caloric restriction, CR）可在跨物种层面稳定延长寿命。然而，CR改善衰老大脑的具体分子与细胞机制仍未明确。本研究通过对小鼠大脑开展时空组学图谱分析，旨在揭示CR发挥抗衰老作用的具体机制。我们分析了来自不同年龄阶段、经CR处理的小鼠大脑样本中超过50万个单细胞的转录状态。通过追踪超过300种转录特征各异的细胞状态的动态变化，我们捕捉到了对衰老尤其易感，以及可被CR挽救的细胞状态的时序动态——例如，CR可延缓炎症性胶质细胞的扩增，并维持神经发生细胞的存活与功能。进一步的空间转录组分析揭示了衰老小鼠经CR处理后，不同脑区的基因表达与细胞动态变化，明确了脑区特异性的抗衰老效应。综上，本研究通过小鼠大脑时空组学图谱分析，勾勒出了响应衰老与CR干预的高度细胞类型特异性分子通路，阐明了CR在不同细胞类型与脑区中发挥的精细化调控作用。