Aging of Hematopoietic Stem Cells - Molecular Architecture of Marrow Dysplasia and Clinical Contribution of Ineffective Hematopoiesis to Frailty in the Elderly

The prevalence and incidence of anemia tend to increase with advancing age. Relatively low hemoglobin concentrations are a common laboratory finding in the elderly, for the most part judged by physicians as a sign without clinical relevance or as a marker of an underlying chronic disease having no independent influence on health. In recent years several studies have started to challenge the widespread and self-perpetuating perception of anemia as an innocent bystander, reporting worse cognitive and quality of life outcomes and increased risk of hospitalization and mortality in the general population. Focusing on elderly people, anemia has a clear association with the phenotypic features of frailty syndrome affecting 3-5% of individuals of 65-70 years of age and, more importantly 30% of those aged 85 years or older. Among frail older adults, anemia is a powerful prognostic factor for the development of frailty-related problems such as muscle weakness, reduced performance, falls, and mortality. Nutrient deficiency, chronic inflammation and renal insufficiency account for the large majority of cases of anemia in the elderly, while underlying cause remained unexplained in 25% of the cases. Preliminary evidence indicates that a significant proportion of ''unexplained anemia'' may account for myelodysplasia(MDS). MDS is a condition typically occurring in elderly people, characterized by clonal proliferation of hematopoietic stem cells (HSC), which partly retain their capacity to differentiate and maturate, but do so in an inefficient manner (ineffective hematopoiesis). Anemia represents the most important prognostic factor in MDS. With time a portion of patients evolve into overt myeloid malignancy (i.e., acute leukemia). Somatic mutations occur in the genomes of healthy HSC at a low, but detectable frequency during normal DNA replication. Although most mutations are rapidly corrected by DNA repair mechanisms, those that persist are propagated during HSC self-renewal.