Understanding intrinsic hematopoietic stem cell aging

Hematopoietic stem cells (HSCs) are sustaining blood production during the whole life of an organism. It is of extreme importance that these cells maintain self-renewal and differentiation potential over time, in order to preserve homeostasis of the hematopoietic system. Many HSC intrinsic aspects are affected by the aging process, leading to the deterioration of the potential of these cells independently of their microenvironment. Here we review recent findings characterizing most of the intrinsic aspects of aged HSCs, ranging from phenotypic to molecular alterations. Historically, DNA damage was thought to be the main responsible for HSC aging. However, in the last years, many new findings have defined an increasing number of biological processes that are intrinsically changing with age in HSCs. Epigenetics and chromatin architecture together with autophagy, proteostasis and metabolic changes and how they are interconnected to each other are acquiring growing importance for understanding the intrinsic aging of stem cells. Since the increasing aging of population worldwide and considering that aging is the primary risk factors for most diseases, understanding HSC aging becomes particularly relevant as well in the context of hematological disorders, such as MDS and AML. Research on intrinsic mechanisms responsible of HSC aging is and will continue to provide new potential molecular targets to possibly ameliorate or delay aging of the hematopoietic system and consequently improve the outcome of hematological disorders in the elderly. The niche-dependent contributions to hematopoietic aging are discussed in another review in this same issue.