This chapter addresses the following Geriatric Curriculum Fellowship Milestone: #9
As with nearly all tissues, the hematopoietic system suffers the consequences of aging, manifested by the emergence of chronic anemia, immune dysfunction, increased incidence of myeloproliferative syndromes, and overt chronic and acute myeloid malignancies. Although hematopoietic stem cells (HSCs) can sustain blood production throughout life, recent studies demonstrate that with aging they undergo dramatic phenotypic and functional changes. This notion is supported by a meta-analysis conducted by the National Marrow Donor Program (NMDP) that assessed multiple donor traits, including donor age, cytomegalovirus serology, ABO blood group compatibility, race, and sex. This study found that advanced donor age is a major negative prognostic factor in clinical outcomes of allogeneic HSC transplant recipients. This is manifested clinically by delayed engraftment; further, molecular HSC microarray studies have revealed that myeloid-specific and chromatin remodeling genes change expression over time. In mouse models, several hallmark age-dependent changes in the HSC compartment have been identified, including an increase in HSC numbers, a decrease in homing capacity, and a myeloid skewing of differentiation potential. Age-related epigenetic dysregulation leads to aberrant gene expression that may contribute to malignant transformation and emergence of myeloid leukemia, which is commonly associated with aging. These results indicate that HSC senescence is not the product of a few programmed genes, but of a large number of genetic changes that affect the entire biological system.
MECHANISMS OF AGING IN THE HEMATOPOIETIC SYSTEM
The hematopoietic system is dependent on a small pool of HSCs (see Figure 103-1), their surrounding microenvironment, and regulatory molecules (ie, hematopoietic growth factors) that dictate cell turnover and maturation. Most studies suggest that alterations in the HSC compartment with age arise at the level of individual HSCs. Hence, fundamental changes in the epigenetic program and signal transduction within these individual cells have been proposed as a mechanism driving functional alterations. Emerging evidence demonstrates that interactions between HSCs and the marrow microenvironment may reveal novel insights of the aging process of the hematopoietic system as outlined below.
Schematic representation of hematopoiesis. Hematopoietic stem cells (HSCs) differentiate into lymphoid proin the bone marrow that give rise to T cells (which develop in the thymus) and B cells, and myeloid progenitors that differentiate to monocytes, dendritic cells, neutrophils, basophils, eosinophils, as well as erythroid and megakaryocytic lineages. Aging is associated with impaired HSC differentiation and repopulation function, and with a bias toward myeloid at the expense of lymphoid progenitors.
Studies conducted in mice more than 20 years ago showed that aged marrow donors can repopulate blood cells in serial hematopoietic transplantation experiments spanning multiple lifetimes, prompting the hypothesis that the HSCs are “effectively ageless.” Clinical observations and recent studies suggest that the ability of human HSCs to ...