Skewed Differentiation Lineages with

Perhaps owing to the overall decline of the immune system during aging briefly discussed above in the Introduction, stem cell transplantation studies have repeatedly shown that engraftment of the immune system is diminished and/or delayed in the face of the enhanced production of myeloid cells, particularly granulocytes and monocytes/macrophages (33, 54, 55). It is worth repeating that during the engraftment process, stem cell function is the net result of intrinsic and extrinsic influences. Cell-autonomous influences, discussed above, include genetic and epigenetic alterations as a function of age, whereas extrinsic influences are manifested via cytokines and other humoral influences but perhaps most importantly through incompletely understood close-range interactions with cells comprising the stem cell "niche" (56) in which stem cells reside. An example of a stem cell-intrinsic change affecting lymphopoiesis is the finding that human CD34+ cells show impaired ability to generate T-cells in culture relative to a similar population from young donors (18). On the extrinsic side of the equation, it has been shown that murine bone marrow stromal cells from old donors, both in vivo and in vitro, demonstrate an impaired capacity to support B-lymphopoiesis (32, 57). Thus, in old age a mechanism or mechanisms involving both intrinsic and extrinsic levels of regulation, acting individually or in concert, skew stem and progenitor cell differentiation away from lymphopoiesis and toward myelopoiesis (see Figs. 1.1 and 1.2). In the context of this volume, it is similarly appealing to ascribe at least part of the anemia of aging to a lineage profile skewing that to some extent sacrifices erythropoiesis in favor of myelopoiesis.

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