Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA.
Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA.
Trends Mol Med. 2019 Jun;25(6):494-515. doi: 10.1016/j.molmed.2019.04.006. Epub 2019 May 17.
Aging leads to functional decline of the hematopoietic system, manifested by an increased incidence of hematological disease in the elderly. Deterioration of hematopoietic integrity with age originates in part from the degraded functionality of hematopoietic stem cells (HSCs). Here, we review recent findings identifying changes in metabolic programs and loss of epigenetic identity as major drivers of old HSC dysfunction and their role in promoting leukemia onset in the context of age-related clonal hematopoiesis (ARCH). We discuss how inflammatory and growth signals from the aged bone marrow (BM) microenvironment contribute to cell-intrinsic HSC aging phenotypes and favor leukemia development. Finally, we address how metabolic, epigenetic, and inflammatory pathways could be targeted to enhance old HSC fitness and prevent leukemic transformation.
衰老导致造血系统功能下降,表现为老年人血液病发病率增加。随着年龄的增长,造血完整性的恶化部分源于造血干细胞(HSCs)功能的降低。在这里,我们回顾了最近的发现,这些发现确定了代谢程序的变化和表观遗传身份的丧失是导致老年 HSC 功能障碍的主要驱动因素,以及它们在与年龄相关的克隆性造血(ARCH)相关的白血病发病中的作用。我们讨论了来自衰老骨髓(BM)微环境的炎症和生长信号如何促进细胞内在的 HSC 衰老表型,并有利于白血病的发展。最后,我们探讨了如何针对代谢、表观遗传和炎症途径来增强老年 HSC 的适应性并预防白血病转化。