A model of age-dependent changes in LT-HSCs. Young LT-HSCs (red; top) maintain an appropriate balance between efficient self-renewal (semi-circular arrow) and differentiation into ST-HSCs (horizontal arrow) that then further differentiate to reconstitute hematopoiesis. In contrast, old LT-HSCs (bottom) are inappropriately shifted toward self-renewal (thick semi-circular arrow) and thereby an accumulation of LT-HSCs (depicted by more copies of old LT-HSCs), ST-HSCs reduction (depicted by less copies of ST-HSCs), and less efficient reconstitution of hematopoiesis (dashed arrow). This can be due to either a short G1, which limits the capacity of old LT-HSCs to receive differentiation signals, or an expression program that resembles a less differentiated state and might reflect defects in differentiation, or both, as these might be causally linked.
