The state of chronic inflammatory signaling in aging is complex, employing many different signaling pathways to regulate the immune system and many different provocations to stimulate those pathways. Hematopoietic stem cells in the bone marrow are responsible for generating immune cells and red blood cells, and their function changes and declines with aging in ways that are similarly complex, driven by many different factors. Here, researchers take a look at one small portion of the intersection between these two complex phenomena, focusing in on the one inflammatory regulator NFκB.
Hematopoietic aging is characterized by chronic inflammation associated with myeloid bias, hematopoietic stem cell (HSC) accumulation, and functional HSC impairment. Yet it remains unclear how inflammation promotes these aging phenotypes. NFκB both responds to and directs inflammation, and we present an experimental model of elevated NFκB activity ("IκB-") to dissect its role in hematopoietic aging phenotypes.
We found that while elevated NFκB activity is not sufficient for HSC accumulation, HSC-autonomous NFκB activity impairs their functionality, leading to reduced bone marrow reconstitution. In contrast, myeloid bias is driven by the IκB- proinflammatory bone marrow milieu as observed functionally, epigenomically, and transcriptomically. A new single cell RNA sequencing framework enabled comparisons with aged murine and human HSC datasets, documenting an association between HSC-intrinsic NFκB activity and quiescence, but not myeloid bias.
These findings delineate separate regulatory mechanisms that underlie the three hallmarks of hematopoietic aging, suggesting that they are specifically and independently therapeutically targetable.
Link: https://doi.org/10.1101/2025.01.14.632900
View the full article at FightAging
