LAUSR

Human hematopoietic stem cells (HSCs), like their counterparts in mice, comprise a functionally and molecularly heterogeneous population of cells throughout life that, collectively, maintain required outputs of mature blood cellsunder homeostatic conditions. An early developmental change in the HSC population in both species includes a postnatal switch from most of these cells existing in a rapidly cycling state and maintenance of a high self-renewal potential to a majority in a quiescent state with an overall reduced self-renewal potential. However, despite the well-established growth factor dependence of HSC proliferation, if and how this mechanism of HSC regulation might be affected by aging has remained poorly understood. To address this gap, we isolated highly HSC-enriched CD34+CD38-CD45RA-CD90+CD49f+ ("CD49f+") cells from cord blood and adult bone marrow and mobilized peripheral blood samples obtained from normal humans spanning 7 decades of age and then measured their functional and molecular responses to growth-factor stimulation in vitro and regenerative activity in vivo in transplanted mice. Initial experiments revealed advancing donor age was accompanied by a significant and progressively delayed proliferative response but not the altered mature cell outputs seen in normal older individuals. Importantly, subsequent dose-response analyses revealed an age-associated reduction in the growth-factor stimulated proliferation of CD49f+ cells mediated by reduced intrinsic activation of AKT and altered cell-cycle entry and progression. These findings identify a new intrinsic, pervasive, and progressive aging-related alteration in the biological and signaling mechanisms required to drive the proliferation of very primitive normal human hematopoietic cells.