Jie Minwen, Feng Tong, Hu Fengjuan, Sun Xuelian, Jia Shuli, Lu Yanrong, Dong Birong, Jiang Hao
Department of Gastroenterology and Hepatology and Laboratory of Aging and Cancer, National Clinical Research Center for Geriatrics and State Key Laboratory of Respiratory Health and Multimorbidity, Key Laboratory of Transplant Engineering and Immunology, NHFPC, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
Sci Rep. 2025 Jul 10;15(1):24828. doi: 10.1038/s41598-025-10421-3.
Frailty, a geriatric syndrome, is characterized by the age-related deterioration of physical capabilities and multiple organ systems. However, its age-associated and age-independent mechanisms remain vague, impeding prevention and clinical intervention. Here, the physical frailty status of young and old mice estimated using the frailty phenotype and frailty index values was used to divide mice into non-frail young/old (NF-Y/NF-O) and frail old (F-O) groups. Age-associated and age-independent transcriptional changes in frailty were investigated using single-cell RNA sequencing to profile transcriptomes in various cell types in limb muscles. We investigated the ratio of cell types, transcriptional regulation networks, and cell-cell communications in 15 major cell types in mice during relatively healthy aging (RHA), age-associated frailty (AAF), and age-independent frailty (AIF). Each group of RHA, AAF or AIF genes exhibited one major expression pattern and transcriptional regulation network. Besides its unique pattern, genes in the AAF group faintly exhibited the two major patterns seen in the AIF and RHA groups. B cells and satellite cells in both the AIF and AAF groups showed the most down-regulated and up-regulated differentially expressed genes, respectively. The transcriptional pattern of B cells, which showed stronger transcriptional changes than satellite cells in the AIF process, was validated by sorting B cells and performing SMART-sequencing. Thus, by analyzing these molecular events at the single-cell level, our study revealed the specific expression patterns and transcriptional heterogeneities of candidate cell types involved in relatively healthy aging and physical frailty, laying a foundation to characterize the detailed mechanisms and presenting possible therapeutic strategies for physical frailty.
衰弱是一种老年综合征，其特征是身体能力和多个器官系统出现与年龄相关的衰退。然而，其与年龄相关和与年龄无关的机制仍不明确，这阻碍了预防和临床干预。在此，利用衰弱表型和衰弱指数值评估年轻和老年小鼠的身体衰弱状态，将小鼠分为非衰弱年轻/老年（NF-Y/NF-O）组和衰弱老年（F-O）组。使用单细胞RNA测序研究衰弱过程中与年龄相关和与年龄无关的转录变化，以分析肢体肌肉中各种细胞类型的转录组。我们研究了相对健康衰老（RHA）、年龄相关衰弱（AAF）和年龄无关衰弱（AIF）过程中小鼠15种主要细胞类型的细胞类型比例、转录调控网络和细胞间通讯。RHA、AAF或AIF基因的每组均表现出一种主要的表达模式和转录调控网络。除了其独特的模式外，AAF组中的基因还微弱地表现出AIF组和RHA组中所见的两种主要模式。AIF组和AAF组中的B细胞和卫星细胞分别显示出差异表达基因下调和上调最多的情况。通过分选B细胞并进行SMART测序，验证了在AIF过程中B细胞比卫星细胞表现出更强转录变化的转录模式。因此，通过在单细胞水平分析这些分子事件，我们的研究揭示了参与相对健康衰老和身体衰弱的候选细胞类型的特定表达模式和转录异质性，为阐明详细机制奠定了基础，并为身体衰弱提供了可能的治疗策略。
