We examined marrow function in the C57B1/6 mouse and in the Senescent Accelerated Mouse (SAM-P6) that is prone to developing age-related osteopenia. In both models, aging is associated with a significant increase in marrow myeloid cell number that is accompanied by increases in colony forming unitadipocyte (CFU-AD) and by significant reductions in CFU-osteoblast(CFU-OB). Histologically murine marrow from older mice (age 24 months) shows increased numbers of fat cells as compared to marrow from the young (age 6 months. In murine long term bone marrow (LTBMC) cultures, the stromal layer forms more rapidly, and, in the early weeks of culture, produces increased numbers of myeloid cells as compared to cultures initiated from young mice. Altered cytokine production may well explain these findings. Compared the young, stroma initiated from old mice produce a 5 fold increase in colony stimulating activity (CSA) and interleukin-6 (IL-6) and significant reductions in the concentrations of transforming growth factor β (TGFβ). Mature neutrophils obtained from LTMBC initiated from old mice demonstrate significant reductions in function, including a decreased ability to generate superoxide and mobilize cytosolic calcium. This reduction of function could be corrected if marrow stem cells were allowed to proliferate and generate mature neutrophils when transplanted from stem cell free stroma generated from young mice. Neutrophil function deteriorated, if stem cells from young mice were transplanted to stroma generated from old animals. These findings provide compelling evidence that stromal factors play a critical role in the age-related alterations in hematopoietic function and in the genesis of age-related osteopenia.