Proposed model for changes in the cellular composition of the HSC compartment with aging. In young mice (left), the frequency of bipotential HSCs is high and thus supports high output of B cells from the BM. With aging (middle), long-lived memory B cells accumulate in the periphery, thus reducing the “need” for production of new B cells. To facilitate this, the HSC composition changes and is dominated by myeloid-only potential HSCs, leaving only a small number of bipotential HSCs. With depletion of the long-lived B cells (right), the peripheral “need” for B cells stimulates expansion of the bipotential HSCs to reactivate B lymphopoiesis in the aged BM and revives the flow of new B cells from the BM to the periphery.