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Intrinsic HSC aging
A focussed understanding of the biology of aging in HSC and new therapeutic approaches is, therefore, mandatory.
Intrinsic aging drivers
Hematopoietic stem cells are the cornerstone of the hematopoietic system. Like other adult stem cells, they need to be localized in special niches that support and con- trol the main stem cell functions: self-renewal and differen- tiation. Since HSC are so critical to the hematopoietic sys- tem and have to be functional during the entire life-span of the organism to maintain blood homeostasis, it is logical to think that somehow they require special protection from aging. Several studies have been trying to address how HSC can endure the effects of aging. However, investigat- ing HSC function in living organisms is extremely challeng- ing, since HSC constitute a rare cell population that, for most of the time, remain quiescent, undergoing very few divisions during the life-span of the organism (reviewed by Chandel et al.5 and Singh et al.6). During aging, changes occur both in the niche, defined as extrinsic, and within the HSC, therefore dependent exclusively on the stem cell itself and, by definition, transplantable.
Working on human aging, especially in the hematopoi- etic system, has important experimental limitations and for this reason most of the research has been performed in model systems, particularly mouse models. Although some aging characteristics can be translated from mice into the human system, some phenotypes and their mech- anistic investigation do not find a parallel in humans. Therefore, the development and establishment of possible new therapies must involve research on humans, or at least on models more similar to humans, such as non- human primates. Throughout this review, we discuss findings obtained in murine studies and we highlight some results obtained from studies carried out also in non- human primates and humans.
In general terms, a set of phenotypic and functional alterations have been consistently reported to characterize aged HSC (Figure 1).
Increase in phenotypic HSC number and decrease regenerative capacity
The number and frequency of HSC in the bone marrow of mice and humans increase with aging, while their regenerative capacity measured in transplantation assays is clearly reduced. It is accepted among researchers that this phenotype is caused primarily by cell-intrinsic mech- anisms,7-9 even though an aged microenvironment can fur- ther aggravate it.10-12
Myeloid skewing
Aged HSC show an increased differentiation potential to the myeloid lineage and a decrease in the potential to differentiate into the lymphoid lineage.9,13,14 Moreover, even though the number of myeloid cells is higher, their quality is compromised.15,16 Interestingly, experiments dealing with single cell transplantations in mice17 and scRNA-sequencing (scRNA-seq) profiling18 have shown that HSC differentiation potential is not as homogenous as it was thought. In particular, “myeloid-restricted repop- ulating progenitors” (MyRP) have been characterized within the young HSC compartment.17 This MyRP sub- population increases dramatically with age, in contrast
with the moderate increase in the amount of multipotent HSC.17,18 Intriguingly, within this MyRP subpopulation, a subset of cells called “latent-HSC” can revert to the multi- potent HSC state upon secondary transplants only in the aged samples.17 Consequently, it would be interesting to know if this subpopulation exists, and if it has the same behavior and features in the human bone marrow as in mice, in order to optimize transplantation therapies involving aged patients. These results highlight the poten- tial importance of single cell profiling, at the molecular and at the cellular level, in order to better characterize also the human HSC compartment.
DNA damage
Accumulation of DNA damage is a common feature of aging in different tissues in many organisms, including humans.19 Although HSC have many mechanisms that enhance their capacity for protecting their genome from DNA alterations,20,21 some specific mutations have been shown to be highly recurrent in HSC.10 In addition, upon aging, some of these somatic mutations are fixed and expand within the aged HSC compartment and are thought to be causally involved in the emergency of spe- cific clones, which are the biggest contributors to replen- ishing the hematopoietic system.22 It is possible that some of these mutated clones could eventually progress to blood malignancies such as MDS or AML, although this is not necessarily the case.23
Clonality
In a young individual, hematopoiesis is normally sup- ported by different HSC clones with similar potential. This has been demonstrated by limiting-dilution trans- plantation experiments.10 However, in the elderly, even though there is an increase in the number of HSC in the bone marrow niche,8 there is a smaller number of HSC clones that disproportionally contribute to the peripheral blood production (reviewed by Akunuru and Geiger2). This phenomenon is termed Clonal Hematopoiesis of Indeterminate Potential (CHIP)24 and is frequently detect- ed in individuals over 55-60 years of age, being associated with an increased risk of hematopoietic malignancies and enhanced cardiovascular risk.25 In recent years, there has been increasing interest in studying how CHIP develops over time and eventually evolves into hematopoietic malignancies, given that this might prove useful in devel- oping therapeutic approaches.23,26
Epigenetic drift
Specific changes occur in the epigenome and chromatin organization of aged HSC compared to young HSC. These changes include DNA methylation,27 specific histone post- translational modifications, and chromatin reorga- nization.28
Cell polarity
Several molecules appear to be polar within the cell and the nucleus in young HSC when compared with aged HSC. For some of these molecules, both their polarity fea- ture and the functional relevance are conserved from Drosophila to humans. In recent years, a few studies have demonstrated that the impairment in the function and stem potential of HSC upon aging are directly related to
the loss of polarity of selected biomolecules within the cell.12,15,29,30
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