Aging and Hematopoiesis

Anemia

By far the most prevalent age-associated hematological condition is anemia. Studies demonstrated that 10% to 24% of elderly individuals develop some form of anemia, where idiopathic cytopenia of unknown significance with isolate anemia (ICUS-A), commonly known as “anemia at older age” is the most prevailing. According to the World Health Organization (WHO), anemia in older individuals occurs when hemoglobin (Hb) levels are less than 13 g/dL in men and less than 12 g/dL in women. Multiple epidemiological studies have associated low Hb levels as risk factors for cardiovascular diseases, cognitive impairment, and insomnia. Furthermore, anemia has been associated with diminished physical performance and more frequent and longer hospitalizations among elderly patients.

The development of anemia at an older age is multifactorial. Malnutrition is the cause of the majority of cases, where deficiency of primarily iron but also folic acid and vitamin B12 hampers RBC production. Specifically in elderly patients, gastrointestinal (GI) tract problems, polypharmacy, and even social isolation have been reported to be significant contributors. Chronic inflammation can also cause anemia, with as many as one-third of patients older than 65 years old displaying a chronic inflammatory state. Common age-related chronic diseases such as chronic kidney disease, rheumatoid arthritis, and different kinds of neoplasms affect systemic inflammatory cytokine levels. These inflammatory cytokines negatively affect erythroid precursors cells in the BM. In addition, erythropoietin (EPO)—the main regulator of erythropoiesis—is usually reduced, leading to decreased RBCs production.

Immunosenescence

Elderly patients often display immunosenescence, which is defined by a reduced ability to combat new pathogens, the accumulation of memory T cells, and a chronic and systemic state of inflammation, termed “inflammaging” (see the discussion in the following sections). One of the proposed causes of a hampered immune response in elderly individuals is the myeloid skewing of aged HSCs. Since myeloid differentiation is favored, the B and T cell population diversity is diminished and the adaptive immune response is impaired. The lack of an adequate immune response in conjunction with a chronic inflammatory state has profound implications and contributes to age-associated clinical manifestations such as susceptibility to infections, diverse types of cancer, autoimmune and neurodegenerative diseases, and atherosclerosis.

Myelodysplastic Syndromes

Elderly individuals may display changes in hematopoiesis which are closely related to bone marrow failure (BMF) syndromes. The most prevalent of these, myelodysplastic syndrome (MDS), is composed of a heterogeneous group of clonal myeloid disorders. This syndrome is characterized by ineffective hematopoiesis, cytopenias—often severe anemia (<10 g/dL)—and dysmyelopoiesis. During normal aging, hematopoiesis displays similar changes as seen in MDS patients, and these pathological findings are associated with an increased risk for transformation into acute myeloid leukemia (AML). Overall, phenotypes associated with normal aging and pathological BMF are generally caused by loss of HSC function, which in turn results in aberrant blood cell formation.

Currently, there are a restricted set of approved drugs for MDS treatment, and none are curative. HSC transplantation is potentially the only curative intervention, but there are significant limitations in terms of donor/recipient compatibility and recipient age-associated comorbidities.

The pathogenesis of MDS has been well studied and specific molecular mechanisms have been identified. Somatic mutations are consistently found in MDS patients and are associated with different prognoses. Mutations in genes such as ASXL1 , EZH2 , RUNX1 , SRSF2 , and TP53 are associated with poor prognosis. Interestingly, some of these genes are also mutated in elderly patients with no clinical manifestations (see the clonal hematopoiesis section). Moreover, the acquisition of somatic mutations in non-hematopoietic cells in the BM microenvironment has been shown to also contribute to niche remodeling, favoring neoplastic hematopoietic progenitors that eventually can initiate disorders such as MDS and AML.