Cellular senescence is a normal consequence of aging that is associated with an impaired ability to respond to stressors, and changes in the expression of various genes, including those involved in DNA repair, have been documented. Interestingly, gene profiling of young and old HSC indicate that the latter do not exhibit changes typically associated with aging in non-blood cells (Rossi et al., 2005
). Instead, age-related defects in the hematopoietic system appear to preferentially affect lymphoid development and leave myelopoiesis relatively unaffected. For example, the expression of lymphoid specific gene sets are significantly reduced in HSC isolated from the bone marrow of old mice, while genes directing myeloid development are upregulated (Rossi et al., 2005
). There may be multiple consequences of these alterations on lymphopoiesis. First, the balance of HSC differentiation may become skewed with age, resulting in the decreased production of early lymphoid progenitors. This event, in turn, would have a cascade effect on the production of all downstream lymphoid progeny. Second, defects in the lymphopoietic potential of HSC may diminish the quality of lymphoid progenitors that are subsequently produced.
In regard to this latter point, changes in HSC may underlie the defects that accumulate in B cell progenitors. For example, it has been demonstrated that aged B cell progenitors have defects that compromise their ability to differentiate efficiently (Johnson et al., 2002a
). In particular, the CLP to pre-pro-B (Min et al., 2006
) and pro-B to pre-B cell (Labrie et al., 2004
; Riley et al., 2005
; Stephan et al., 1996
) transitions seem particularly compromised in old mice. In addition, the proliferative potential of CLP, pre-pro-B, and pro-B cells isolated from the bone marrow of old mice is markedly reduced (Min et al., 2006
), and pro-B cells isolated from old mice do not efficiently respond to the lymphopoietic cytokine interleukin-7 (IL-7) (Miller and Allman, 2003
; Stephan et al., 1997
). Similarly, adult bone marrow derived B-1 B cell progenitors are significantly less responsive to thymic stromal lymphopoietin (TSLP), another stromal derived cytokine to which B lineage cells respond, compared to their fetal counterparts (Montecino-Rodriguez et al., 2006
). Thus, the proliferative and differentiative defects in hematopoietic progenitors that accrue with age are seemingly responsible for the reduced number of B cell progenitors present in the bone marrow of older mice.
In addition to intrinsic hematopoietic defects, alterations in the bone marrow microenvironment may also hinder the efficient production of B lineage cells. For example bone marrow stromal cells isolated from old mice inefficiently secrete IL-7 (Heng et al., 2005
; Stephan et al., 1998
). A recent study reported that the production of B cells was rescued following transplantation of aged B lineage progenitors into a young but not an old environment (Labrie et al., 2004
). The implication of this study is that the age-related decline in B lymphopoiesis is entirely the product of extrinsic environmental changes. The fact that environmental alterations contribute to the age-related decline in lymphopoiesis is not in contention, but the assertion that they are exclusively responsible for said decline is difficult to reconcile with the abundance of lymphoid progenitor intrinsic defects discussed previously.