Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types

Aging is a complex process involving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. Recent studies using heterochronic parabiosis have shown that various aspects of aging-associated decline are modifiable or even reversible. To better understand how this occurs, we performed single-cell transcriptomic profiling of young and old mouse brains following parabiosis. For each cell type, we catalogued alterations in gene expression, molecular pathways, transcriptional networks, ligand-receptor interactions, and senescence status. Our analyses identified gene signatures demonstrating that heterochronic parabiosis regulates several hallmarks of aging in a cell-type-specific manner. Brain endothelial cells were found to be especially malleable to this intervention, exhibiting dynamic transcriptional changes that affect vascular structure and function. These findings suggest novel strategies for slowing deterioration and driving regeneration in the aging brain through approaches that do not rely on disease-specific mechanisms or actions of individual circulating factors. Total of 56 mouse brains with raw and processed data for 158,767 cells and filtered data for 50 mouse brains and 105,329 cells.衰老是一个复杂的生物学过程，涉及包括大脑在内的多种组织器官中与机能衰退相关的转录组改变。既往利用异时共生（heterochronic parabiosis）开展的研究表明，衰老相关机能衰退的诸多方面可被修饰甚至逆转。为深入阐明该现象的内在机制，本研究对经历异时共生实验的年轻与老年小鼠大脑开展了单细胞转录组谱分析（single-cell transcriptomic profiling）。针对每一类细胞，我们系统梳理了其基因表达、分子通路、转录调控网络、配体-受体相互作用以及衰老状态的改变。本研究的分析结果鉴定出一系列基因特征，证实异时共生可通过细胞类型特异性的方式调控衰老的若干标志性特征。其中，脑内皮细胞（brain endothelial cells）对该干预手段的响应尤为显著，呈现出影响血管结构与功能的动态转录组变化。本研究结果为通过不依赖疾病特异性机制或单一循环因子作用的策略，延缓衰老大脑的机能衰退并促进其再生提供了全新的思路。本数据集共包含56颗小鼠大脑的原始及处理后数据（对应158767个细胞），以及50颗小鼠大脑的过滤后数据（对应105329个细胞）。