Multimodal omics identifies a lymphoid-biased multipotent progenitor population with limited age-associated remodeling

Hematopoietic aging is marked by declining regenerative capacity and a shift from lymphoid to myeloid output. Previous studies have focused primarily on hematopoietic stem cells (HSCs), yet whether aging uniformly remodels the hematopoietic stem and progenitor cell (HSPC) compartment, or selectively affects distinct populations, remains largely unknown. To address this, we profile HSCs and multipotent progenitors MPP1-6 from young and aged mice across transcriptomic, epigenomic, metabolomic and lipidomic layers, together with single-cell division and in vivo serial transplantation assays. We identify young MPP6 (negative for CD150, CD34, CD48 and CD135) as an HSC-like, lymphoid-biased population with long-term reconstitution capacity, positioned within the top-tier of the differentiation hierarchy and marked by low global chromatin accessibility and metabolic activity. Upon aging, MPP6 preserved long-term lymphoid reconstitution, underwent limited transcriptional and regulatory remodeling, and did not accumulate polyunsaturated phospholipids or show mitochondrial oxidation. By contrast, most HSPCs, and particularly HSCs, underwent pronounced age-associated changes, including myeloid-biased expansion, metabolic rewiring, extensive distal regulatory alteration and accumulation of long-chain polyunsaturated phospholipids linked to increased oxidative stress. Pseudotime analysis further resolved the aged MPP6 compartment into two subsets, including a dormant, lymphoid-biased Dlk1-expressing population characterized by reduced mitochondrial activity, which was distinctly affected by inflammatory challenge in vivo. Together, these findings establish MPP6 as a comparatively resilient population within the aged HSPC compartment and suggest that it may represent a potential target for restoring hematopoietic balance.