Figure 3 |. Inflammatory and aging-associated drivers of HSC functional alterations.

a | Hematopoietic stem cells (HSCs) express Toll-like receptors (TLRs) that directly respond to pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) that is detected by TLR4. Moreover, HSCs express receptors for cytokines, including IL-1β, and for growth factors, such as M-CSF. These stimuli can drive the proliferation and differentiation of HSCs and downstream progenitors, such as multipotent progenitors (MPPs) and granulocyte-monocyte progenitors (GMPs), leading to enhanced myelopoiesis^61–63. This myeloid-biased differentiation can be protective in certain contexts like acute infections, but chronic inflammatory exposure to these and other infection-associated or inflammatory stimuli can cause functional impairment in HSCs^1,24,63. b | With aging, HSCs undergo functional changes including altered lineage output. This age-associated skewing favors differentiation toward the myeloid and megakaryocytic lineages — resulting in increased production of neutrophils, monocytes/macrophages, and platelets — while diminishing lymphoid output (B and T lymphocytes)^68,69. The myeloid bias contributes to a pro-inflammatory systemic environment, often referred to as ‘inflammaging’, while the decline in lymphopoiesis compromises adaptive immunity. c | In old age, HSCs not only exhibit altered lineage output (panel b), but also show impaired self-renewal capacity and increased vulnerability to apoptosis or cellular senescence⁷⁶. This functional decline is in great part attributed to intrinsic aging-associated alterations within HSCs. Such changes include upregulated pro-inflammatory signalling and stress responses — marked by elevated levels of reactive oxygen species (ROS) and activation of the mechanistic target of rapamycin (mTOR) pathway⁷³ — as well as a diminished ability to perform autophagy⁷⁴. Additionally, aged HSCs demonstrate reduced efficiency in repairing DNA damage⁷⁵ and exhibit epigenetic dysregulation due to aberrant chromatin remodelling^78,79. d | With age, HSCs may acquire somatic mutations that enhance self-renewal, leading to clonal expansion of mutant leukocytes—a condition known as clonal hematopoiesis of indeterminate potential (CHIP). These mutations, often loss-of-function, arise from missense changes in critical domains, nonsense mutations, or small insertions/deletions (top panel). The most frequently affected genes encode the enzymes DNMT3A (DNA methyltransferase 3A), TET2 (Ten-eleven translocation methylcytosine dioxygenase-2), and ASXL1 (Additional sex combs-like 1). DNMT3A and TET2 act on DNA and regulate cytosine methylation and demethylation, respectively, whereas ASXL1, as part of the polycomb repressive complex-2, modifies histones by mediating trimethylation of histone H3 at lysine 27 (H3K27) (lower panels)^5,147. Given that the affected genes encode epigenetic regulators, their inactivation in HSCs disrupts transcriptional control, promoting clonal dominance, altering leukocyte phenotypes, and increasing the risk of age-related diseases.