Caloric restriction reprograms the single-cell transcriptional landscape of Rattus norvegicus aging

Aging causes a functional decline in tissues throughout the body that may be delayed by caloric restriction (CR). However, the cellular profiles and signatures of aging, as well as those ameliorated by CR, remain unclear. Here, we built comprehensive single-cell and single-nucleus transcriptomic atlases across various rat tissues undergoing aging and CR. CR attenuated aging-related changes in cell type composition, gene expression, and core transcriptional regulatory networks. Immune cells were increased during aging, and CR favorably reversed the aging-disturbed immune ecosystem. Computational prediction revealed that the abnormal cell-cell communication patterns observed during aging, including the excessive proinflammatory ligand-receptor interplay, were reversed by CR. Our work provides multi-tissue single-cell transcriptional landscapes associated with aging and CR in a mammal, enhances our understanding of the robustness of CR as a geroprotective intervention, and uncovers how metabolic intervention can act upon the immune system to modify the process of aging.衰老是导致全身各组织功能衰退的核心诱因，而热量限制（caloric restriction, CR）可延缓这一进程。然而，衰老相关的细胞特征与分子标记，以及热量限制所改善的相关特征，目前仍未完全阐明。本研究构建了针对衰老及热量限制处理的多种大鼠组织的综合单细胞转录组（single-cell transcriptomic）及单细胞核转录组（single-nucleus transcriptomic）图谱。热量限制可缓解细胞类型组成、基因表达及核心转录调控网络中与衰老相关的异常改变。衰老过程中免疫细胞占比升高，而热量限制可有效逆转衰老所扰乱的免疫微生态系统。计算预测分析显示，衰老过程中出现的异常细胞间通讯模式，包括过度的促炎配体-受体相互作用，可被热量限制逆转。本研究提供了哺乳动物中与衰老及热量限制相关的多组织单细胞转录组景观，加深了我们对热量限制作为抗衰老干预手段的有效性的认知，并揭示了代谢干预如何通过作用于免疫系统以调控衰老进程。