Singh Abhishek K, Althoff Mark J, Cancelas Jose A
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center.
Hoxworth Blood Center, University of Cincinnati College of Medicine.
Curr Stem Cell Rep. 2018 Jun;4(2):166-181. doi: 10.1007/s40778-018-0128-6. Epub 2018 May 1.
Functional decline of hematopoiesis that occurs in the elderly, or in patients who receive therapies that trigger cellular senescence effects, results in a progressive reduction in the immune response and an increased incidence of myeloid malignancy. Intracellular signals in hematopoietic stem cells and progenitors (HSC/P) mediate systemic, microenvironment, and cell-intrinsic effector aging signals that induce their decline. This review intends to summarize and critically review our advances in the understanding of the intracellular signaling pathways responsible for HSC decline during aging and opportunities for intervention.
For a long time, aging of HSC has been thought to be an irreversible process imprinted in stem cells due to the cell intrinsic nature of aging. However, recent murine models and human correlative studies provide evidence that aging is associated with molecular signaling pathways, including oxidative stress, metabolic dysfunction, loss of polarity and an altered epigenome. These signaling pathways provide potential targets for prevention or reversal of age-related changes.
Here we review our current understanding of the signalling pathways that are differentially activated or repressed during HSC/P aging, focusing on the oxidative, metabolic, biochemical and structural consequences downstream, and cell-intrinsic, systemic, and environmental influences.
老年人或接受引发细胞衰老效应治疗的患者中发生的造血功能衰退，会导致免疫反应逐渐降低以及髓系恶性肿瘤发病率增加。造血干细胞和祖细胞（HSC/P）中的细胞内信号介导系统性、微环境和细胞内在效应衰老信号，从而导致它们的衰退。本综述旨在总结并批判性地回顾我们在理解衰老过程中导致HSC衰退的细胞内信号通路以及干预机会方面取得的进展。
长期以来，由于衰老的细胞内在性质，HSC衰老一直被认为是干细胞中不可逆转的过程。然而，最近的小鼠模型和人类相关研究提供了证据，表明衰老与分子信号通路有关，包括氧化应激、代谢功能障碍、极性丧失和表观基因组改变。这些信号通路为预防或逆转与年龄相关的变化提供了潜在靶点。
在此，我们回顾了目前对HSC/P衰老过程中差异激活或抑制的信号通路的理解，重点关注下游的氧化、代谢、生化和结构后果，以及细胞内在、系统性和环境影响。
