Abstract

Aging hematopoiesis exhibits progressive myeloid skewing and impaired lymphopoiesis, driving age-related blood disorders. We show that multipotent progenitors (MPPs) mediate this lineage imbalance. Aging expands myeloid-biased MPP3 cells while functionally compromising MPP4 lymphoid potential, collectively skewing hematopoietic output toward the myeloid lineage. We identify Bcl11a as a dosage-sensitive regulator of MPP fate: Bcl11a suppresses Fer to restrain premature myeloid differentiation in MPP3, while activating the Irf8-Ebf1 axis to license lymphoid specification. Strikingly, sustained Bcl11a elevation from development preserves balanced lineage output into old age, reverses age-associated transcriptional alterations, and restores multilineage reconstitution capacity. These findings establish Bcl11a as a key molecular guardian of progenitor integrity during aging and underscore MPPs as a critical cellular nexus where transcriptional control translates into lineage fate decisions.