Introduction:
As the individual ages, the bone marrow undergoes significant changes with clinical implications. These alterations, observed in both animals and humans, encompass shifts in cell count, senescence, lineage differentiation, cellular composition, and hematopoietic stem cell (HSC) function. These changes contribute to a higher incidence of cytopenias, particularly anemia and lymphopenia, and an increased risk of hematological malignancies.
Stem cells naturally accumulate mutations during reproduction, leading to clonal hematopoiesis. Not all mutations in HSCs are inherently pathological, as they commonly accumulate over time. Clonal hematopoiesis of indeterminate potential refers to the presence of somatic mutations in genes associated with myeloid hematological disorders and is prevalent in the aging population. Whether CHIP is a disease or a facet of normal aging remains unclear. Population studies suggest an association between CHIP and the development of hematological malignancies (both lymphoid and myeloid) as well as atherosclerosis (cardiovascular and cerebrovascular diseases).
What Is Hematopoiesis?
Hematopoiesis is a dynamic and continuous process involving the production and utilization of mature blood cells within the hemato-lymphoid system. In a healthy individual weighing 154 pounds, approximately 5*10^11 mature blood cells are generated daily throughout their lifetime. All blood cells originate from a small population of hematopoietic stem cells (HSCs) in the bone marrow, possessing the unique abilities of self-renewal-generating themselves and multi-lineage differentiation– producing various blood cell types, including red blood cells, platelets, monocytes, granulocytes, natural killer (NK) cells, B cells, and T cells.
While most adult HSCs are typically quiescent in the GO phase of the cell cycle during steady-state conditions, turning over slowly every month, the daily hematopoietic production is primarily sustained by highly proliferative downstream, hematopoietic progenitor cells (HPCs).
The behavior of HSCs, including self-renewal, differentiation, and apoptosis, is intricately regulated by intrinsic factors such as transcription, regulatory networks, and cellular metabolism and extrinsic factors like cytokines, chemokines, growth factors, metabolites, and external pathogen-derived molecules. In response to hematopoietic challenges requiring the replenishment of mature blood cells, HSCs can interpret local or systematically migrating external signals, enhancing their proliferation and differentiation.
What Are the Changes Seen in Blood Count With Aging?
Anemia is commonly seen among the elderly, affecting 11 percent of men and 10 percent of women ages 65 and older, with various contributing factors. Common causes include anemia of chronic diseases linked to inflammation, chronic kidney disease, nutritional deficiencies (iron, vitamin B12, and folate), and clonal disorders like myelodysplastic syndrome (MDS).
While no specific decline in the erythroid population has been identified in marrow evaluations, elevated levels of erythropoietin (EPO), a hormone-stimulating erythropoiesis, are noted. Aging may lead to a decreased response to EPO, requiring higher levels to maintain normal hemoglobin. In inflammatory disorders, lower EPO concentrations suggest reduced hormonal stimulation, contributing to anemia.
An increased white blood cell count serves as an independent marker of all-cause mortality, particularly associated with cancer or cardiovascular-related death, across all populations, including the elderly. Leukocytosis may indicate generalized inflammation.
Monocyte levels rise with age and in murine models, aged mice’s monocytes promote intimal hyperplasia, a feature of atherosclerosis, compared to young mice’s monocytes. Aged human monocytes show altered phenotypes and surface markers, shifting from classical CD14+CD16- to nonclassical CD14+CD16+. These nonclassical monocytes secrete proinflammatory cytokines, but the consequences of this secretion remain unknown.
What Hematopoietic Changes Occur During Aging?
The aging of the hematopoietic system is characterized by functional declines in both the adaptive and innate immune systems, resulting in immunosenescence. This age-related phenomenon renders individuals highly susceptible to infections, reduces the efficacy of vaccinations, and increases vulnerability to autoimmunity and hematologic malignancies. Some hematopoietic changes during aging include:
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Significant reductions in B cell production led to a decrease in the naive B cell pool and an expansion of the memory B cell pool. The B cell repertoire’s diversity decreases, accompanied by lowered antibody affinity and impaired class switching, making B cells more prone to producing auto-antibodies and increasing the risk of spontaneous autoimmunity.
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Decline in de novo T cell production with aging, party attributed to thymic involution. CD8+ T cells undergo oligoclonal expansion, and their repertoire becomes skewed toward previously encountered antigens as neches for naive T cells in peripheral lymphoid tissues are occupied by terminally differentiated cells.
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Diminished cytotoxicity and cytokine secretion in NK cells.
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Although myeloid cells increase in number, their functionality decreases. Neutrophils migrate less in response to stimuli, and macrophages exhibit reduced phagocytic activity and decreased oxidative burst.
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The decline in erythropoiesis in the elderly leads to frequent anemia, while the thrombocytic lineage, to date, has not been reported to be significantly affected by aging.
Bone Marrow Changes During Aging:
The hematopoietic stem cell (HSC) homeostasis in the bone marrow (BM) microenvironment, or HSC niche, is crucial for HSC self-maintenance. Recent studies highlight a perivascular HSC niche composed of mesenchymal stromal cells (MSC) and endothelial cells (ECs) that reflects hierarchical HSC function and age-related effects.
In aging, MSCs within the niche exhibit reduced clonogenic and proliferative capacity, skewed differentiation towards adipogenesis, and various age-related features such as telomere shortening, DNA damage, and elevated reactive oxygen species and nitric oxide. Molecular changes, including activating specific receptors, contribute to enhanced adipogenesis in aged BM, associated with dysregulated insulin growth factor signaling and altered extracellular matrix composition.
Increased adipogenesis negatively impacts HSC function and B-lymphopoiesis, favoring myelopoiesis over lymphopoiesis. Young HSCs in an aged environment tend to produce more myeloid cells than in a young environment.
Endothelial cells in the HSC niche secrete factors crucial for HSC maintenance. Aging leads to decreases in specific EC-associated cells and structures, resulting in reduced stem cell factor production. Activating endothelial notch signaling can reverse age-related vascular niche alterations without affecting aged HSC function. Vascular endothelial function declines with aging due to reduced nitric oxide, potentially impacting HSC mobilization mediated by CXCL12.
Age-related reductions in endothelial cells-derived nitric oxide changes in the angiogenic function of the bone marrow niche may contribute to aberrant HSC maintenance and/or retention in aged BM. Overall, understanding these niche dynamics is essential for addressing age-related hematopoietic changes.
Conclusion:
Aging exerts profound effects on hematopoiesis, disrupting the delicate balance of the hematopoietic stem cell (HSC) niche, particularly involving mesenchymal stromal cells (MSCs) and endothelial cells (ECs), undergoes significant alterations with age. These changes include reduced HSC functionality, skewed differentiation towards myeloid lineages, and an increased propensity for adipogenesis. The decline in the adaptive and innate immune responses, known as immunosenescence, contributes to heightened susceptibility to infections, decreased vaccine efficacy, and an elevated risk of hematologic malignancies.
