Aging, hematopoiesis, and the myelodysplastic syndromes

Abstract

The aging hematopoietic system undergoes numerous changes, including reduced production of red blood cells and lymphocytes as well as a relative increase in the production of myeloid cells. Emerging evidence indicates that many of these changes are due to selection pressures from cell-intrinsic and cell-extrinsic factors that result in clonal shifts in the hematopoietic stem cell (HSC) pool, resulting in predominant HSC clones that exhibit the functional characteristics associated with HSC aging. Given the recent descriptions of clonal hematopoiesis in aged populations, the increased risk of developing hematologic malignancies in individuals with clonal hematopoiesis, and the many similarities in hematopoietic aging and acquired bone marrow failure (BMF) syndromes, such as myelodysplastic syndromes (MDS), this raises significant questions regarding the relationship between aging hematopoiesis and MDS, including the factors that regulate HSC aging, whether clonal hematopoiesis is required for the development of MDS, and even whether BMF is an inevitable consequence of aging. In this article, we will review our current understanding of these processes and the potential intersections among them.

Figure 1.

The features of HSCs in the context of aging and MDS are shown. With normal aging, there is an increase in the risk of the development of CHIP, but the contributions of and requirement for CHIP in aging phenotypes remain incompletely understood. Many functional characteristics of aged HSCs are accentuated in MDS, but the molecular events necessary to transition from CHIP to the clinically significant cytopenias seen in MDS remain unclear.