Aging and neoteny in the B lineage

Abstract

Aging and the physiologic decline of tissues and cells were once thought to be irreversible. However, recent studies suggest that various tissues, especially parts of the hematopoietic system, can be rejuvenated. Here we review potential mechanisms for this process and how they may be used to reverse age-related disorders and aging in general. We propose the novel hypothesis that altering the homeostatic process during cellular depletion can reverse aging in the hematopoietic system.

Figure 1

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.

Figure 2

Regeneration of B cells in mice after depletion. Old mice were treated for multiple rounds of B-cell depletion and were followed for the kinetics of B-cell return by analysis of peripheral blood. The second and the third depletion events were introduced only after > 80% reconstitution was achieved. Gray bars represent the average time for B-cell reconstitution after each depletion, and black bar, the time needed for B-cell reconstitution in young mice. These data summarize the experiments of Keren et al.