Inflammation Drives Blood Cell Aging Through Two Separate Mechanisms Scientists Just Untangled

Hematopoietic aging — the decline of the blood and immune system with age — is characterized by three overlapping hallmarks: chronic inflammation, myeloid bias (overproduction of inflammatory myeloid cells at the expense of lymphoid cells), and accumulation of hematopoietic stem cells (HSCs) that paradoxically lose function. These changes are linked to increased susceptibility to infection, anemia, clonal hematopoiesis, and myeloid malignancies. NF-κB, a master transcription factor governing inflammatory responses, is known to be elevated in aged HSCs, but whether it is a cause or consequence of these changes — and whether it acts within HSCs or their surrounding niche — has been unclear.

Researchers at UCLA developed a compound IκB-deficient mouse model (IκB⁻: Nfkbia⁺/⁻ Nfkbib⁻/⁻ Nfkbie⁻/⁻) that lacks key inhibitors of NF-κB, resulting in elevated inflammatory NF-κB activity throughout all tissues. Young IκB⁻ mice recapitulated the inflammatory bone marrow cytokine profile of aged wild-type mice, with dramatically elevated levels of TNF, IL-1α, CCL5, CSF3, and eotaxin. They showed increased myeloid-biased MPP3 and MPP2 progenitors, peripheral granulocytosis, reduced B cells, and more circulating myeloid cells — mirroring aged hematopoiesis. Notably, however, LT-HSC numbers were not increased in IκB⁻ mice, unlike in naturally aged mice, indicating that NF-κB elevation alone is not sufficient to drive HSC accumulation.

To separate the roles of HSC-intrinsic vs. milieu (niche) NF-κB activity, the team performed bone marrow chimera experiments: wild-type donor marrow was transplanted into IκB⁻ or wild-type recipients. After 15 weeks, genetically normal donor HSCs residing in an IκB⁻ inflammatory milieu showed significantly increased MPP3 (myeloid-biased progenitor) abundance and peripheral myeloid output, demonstrating that the inflamed niche is sufficient to drive myeloid bias in otherwise normal stem cells. Critically, when these myeloid-biased donor cells were re-transplanted into healthy wild-type secondary recipients, myeloid bias fully resolved within 16 weeks — proving that niche-driven myeloid skewing is epigenetically reversible, not hardwired into the stem cells.

ATAC-seq chromatin accessibility profiling of sorted HSPC subsets revealed the mechanism: the inflamed IκB⁻ milieu drove marked opening of C/EBP transcription factor motifs specifically in HSCs (not just in downstream MPP3 progenitors), epigenomically priming them toward myeloid output. This chromatin remodeling was milieu-dependent rather than a cell-autonomous change, consistent with the reversibility seen upon re-transplantation. RNA sequencing of HSCs from IκB⁻ mice showed upregulation of quiescence and cell cycle arrest genes, while functional transplantation assays demonstrated that IκB⁻ HSCs provided significantly reduced bone marrow reconstitution compared to wild-type HSCs — confirming HSC-intrinsic NF-κB drives functional impairment and quiescence independently of myeloid bias.

Finally, a single-cell RNA sequencing framework was used to compare HSPC signatures in this model with published aged murine and human HSC datasets. HSC-intrinsic NF-κB transcriptomic signatures associated with quiescence were conserved across aged mice and aged human HSCs, while milieu-driven epigenomic myeloid bias signatures were also detectable in aged animals. Together, the findings establish that the three hallmarks of hematopoietic aging — HSC accumulation, myeloid bias, and HSC functional decline — are mechanistically separable, each with distinct drivers: HSC accumulation is not caused by NF-κB; myeloid bias is driven by the inflamed milieu via epigenomic reprogramming; and HSC functional impairment is driven by HSC-intrinsic NF-κB activity promoting quiescence.