Department of Neurology, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, 315040, Zhejiang, China.
Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
Geroscience. 2022 Aug;44(4):2139-2155. doi: 10.1007/s11357-022-00578-4. Epub 2022 May 11.
Aging is a progressive loss of physiological function and increased susceptibility to major pathologies. Degenerative diseases in both brain and bone including Alzheimer disease (AD) and osteoporosis are common in aging groups. TERC is RNA component of telomerase, and its deficiency accelerates aging-related phenotypes including impaired life span, organ failure, bone loss, and brain dysfunction. In this study, we investigated the traits of bone marrow-brain cross-tissue communications in young mice, natural aging mice, and premature aging (TERC deficient, TERC-KO) mice by single-cell transcriptome sequencing. Differentially expressed gene analysis of brain as well as bone marrow between premature aging mouse and young mouse demonstrated aging-related inflammatory response and suppression of neuron development. Further analysis of senescence-associated secretory phenotype (SASP) landscape indicated that TERC-KO perturbation was enriched in oligodendrocyte progenitor cells (OPCs) and hematopoietic stem and progenitor cells (HSPC). Series of inflammatory associated myeloid cells was activated in premature aging mice brain and bone marrow. Cross-tissue comparison of TERC-KO mice brain and bone marrow illustrated obvious ligand-receptor communications between brain glia cells, macrophages, and bone marrow myeloid cells in premature aging-induced inflammation. Enrichment of co-regulation modules between brain and bone marrow identified premature aging response genes such as Dusp1 and Ifitm3. Our study provides a rich resource for understanding premature aging-associated perturbation in brain and bone marrow and supporting myeloid cells and endothelial cells as promising therapy targeting for age-related brain-bone diseases.
衰老是生理功能的逐渐丧失和对主要病理的易感性增加。大脑和骨骼中的退行性疾病，包括阿尔茨海默病（AD）和骨质疏松症，在老年人群中很常见。TERC 是端粒酶的 RNA 成分，其缺乏加速了与衰老相关的表型，包括寿命缩短、器官衰竭、骨丢失和大脑功能障碍。在这项研究中，我们通过单细胞转录组测序研究了年轻小鼠、自然衰老小鼠和早衰（TERC 缺陷，TERC-KO）小鼠骨髓-脑跨组织通讯的特征。对早衰小鼠和年轻小鼠的大脑和骨髓中的差异表达基因分析表明，与衰老相关的炎症反应和神经元发育受到抑制。对衰老相关分泌表型（SASP）景观的进一步分析表明，TERC-KO 扰动在少突胶质前体细胞（OPC）和造血干细胞和祖细胞（HSPC）中富集。在早衰小鼠的大脑和骨髓中，一系列与炎症相关的髓样细胞被激活。TERC-KO 小鼠大脑和骨髓的跨组织比较表明，在早衰诱导的炎症中，大脑神经胶质细胞、巨噬细胞和骨髓髓样细胞之间存在明显的配体-受体通讯。大脑和骨髓之间的共调控模块的富集确定了早衰反应基因，如 Dusp1 和 Ifitm3。我们的研究为理解大脑和骨髓中与早衰相关的扰动提供了丰富的资源，并支持髓样细胞和内皮细胞作为治疗与年龄相关的脑-骨疾病的有前途的靶点。
