Stem cells and aging in the hematopoietic system

Abstract

The effector cells of the blood have limited lifetimes and must be replenished continuously throughout life from a small reserve of hematopoietic stem cells (HSCs) in the bone marrow. Although serial bone marrow transplantation experiments in mice suggest that the replicative potential of HSCs is finite, there is little evidence that replicative senescence causes depletion of the stem cell pool during the normal lifespan of either mouse or man. Studies conducted in murine genetic models defective in DNA repair, intracellular ROS management, and telomere maintenance indicate that all these pathways are critical to the longevity and stress response of the stem cell pool. With age, HSCs show an increased propensity to differentiate towards myeloid rather than lymphoid lineages, which may contribute to the decline in lymphopoiesis that attends aging. Challenges for the future include assessing the significance of 'lineage skewing' to immune dysfunction, and investigating the role of epigenetic dysregulation in HSC aging.

Figure 1. Proposed HSC aging mechanisms and their relationship to blood aging phenotypes

Stem cells accrue DNA damage with age, while the slow cycling of the HSC pool results in telomere erosion. To contain the risk of oncogenesis, cells have defense mechanisms which can sense genomic damage and trigger programmed cell death or permanent cell cycle arrest (apoptosis and cellular senescence). As the burden of unrepaired damage in the stem cell pool increases, the frequency with which these pathways are activated in HSCs and their downstream progeny rises, and average HSC regenerative potential falls. Although this does not lead to stem cell exhaustion in normal aging, the reserve capacity to meet hematopoietic stress is reduced. Genomic damage and epigenetic instability can also lead to malignant transformation of HSCs, progenitors or effector cells, manifesting acutely as cancer or chronically as myeloproliferative disorders. Changes in gene expression with age alter the propensity for HSCs to differentiate towards different blood cell lineages, a phenomenon known as ‘lineage skewing.’ Lymphoid progenitor numbers are reduced in old age, contributing to a fall in the production of naïve B and T cells. A shift in the peripheral lymphocyte population towards antigen-experienced memory cells and away from naïve cells underwrites the declining response to infection which typifies immunosenescence.