Understanding intrinsic hematopoietic stem cell aging

Abstract

Hematopoietic stem cells (HSC) sustain blood production over the entire life-span 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 of the intrinsic aspects of HSC are affected by the aging process resulting in a deterioration in their potential, independently of their microenvironment. Here we review recent findings characterizing most of the intrinsic aspects of aged HSC, ranging from phenotypic to molecular alterations. Historically, DNA damage was thought to be the main cause of HSC aging. However, over recent years, many new findings have defined an increasing number of biological processes that intrinsically change with age in HSC. Epigenetics and chromatin architecture, together with autophagy, proteostasis and metabolic changes, and how they are interconnected, are acquiring growing importance for understanding the intrinsic aging of stem cells. Given the increase in populations of older subjects worldwide, and considering that aging is the primary risk factor for most diseases, understanding HSC aging becomes particularly relevant also in the context of hematologic disorders, such as myelodysplastic syndromes and acute myeloid leukemia. Research on intrinsic mechanisms responsible for HSC aging is providing, 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 hematologic disorders in the elderly. The niche-dependent contributions to hematopoietic aging are discussed in another review in this same issue of the Journal.

Figure 1.

Intrinsic hallmarks of hematopoietic stem cells (HSC) aging. (A) Representative features of young HSC. (B) Representative features of aged HSC. K16ac: H4K16ac; met: DNA methylated; green me3: H3K4me3; red me3: H3K27me3. ROS: Reactive oxidative species; PRC2: Polycomb Repressive Complex 2.

Figure 2.

The nuclear compartment in hematopoietic stem cells (HSC) during aging. The nuclear compartment undergoes several changes through aging, ranging from changes in histone post-translational modifications and DNA methylation to alterations of epi-polarity and chromatin architecture. Although the DNA damage repair (DDR) machinery is functional when entering in cycle from quiescence, DNA mutation and hematopoietic clonality can be detected and increase in frequency over time. CASIN treatment of aged HSC restores epi-polarity of H4K16ac, a nuclear hallmark of young HSC. K16ac: H4K16ac; met: DNA methylated; green me3: H3K4me3; red me3: H3K27me3. DDR: DNA damage repair.

Figure 3.

Metabolic homeostasis and proteostasis during aging in hematopoietic stem cells (HSC). Young HSC fine-tune several biological processes: they maintain a low metabolic rate, control protein degradation and regulate autophagy. Aged HSC show an unbalanced scenario where these processes lose their metabolic home-ostasis and proteostasis, converging into a status of metabolic and protein stress. Fasting is able to restore at least partially the activity of the UPR^ER and proteostasis in aged HSC. ROS: reactive oxygen species; UPR: unfolded protein response.

Figure 4.

Interconnections between different biological processes involved in intrinsic hematopoietic stem cell (HSC) aging. We have defined five biological processes affected during aging that cannot be compartmentalized from each other. They are interconnected and a change in one of the processes might affect the others, and all of them converge in the final outcome of intrinsic aging. Specific documented interconnections between different biological processes involved in intrinsic HSC aging are numbered (1 to 10).