Aging is generally considered a progressive and irreversible process. Age-related alterations in the immune system result in increased susceptibility to infectious diseases and poor responsiveness to vaccination. Recently, several studies have suggested that age-related alterations in hematopoietic and non-hematopoietic tissues can be reversed. In this article we review possible mechanisms for aging in the B lineage and propose a novel hypothesis: altering cellular homeostasis by depletion can reverse aging by reactivating B lymphopoiesis in the bone marrow and rejuvenating the peripheral B cell compartment.