Aging hematopoietic system: Mechanisms, disorders, and therapeutic frontiers
Year: 2025
Type: editorial
Abstract: The hematopoietic system stands as a cornerstone of organismal physiology, maintaining lifelong blood cell production while serving critical roles in immune defense and tissue homeostasis. With advancing age, this precisely regulated system undergoes progressive functional decline, driven by interconnected changes in hematopoietic stem cells (HSCs), their bone marrow (BM) niche, and systemic factors, all of which contribute to aging-related hematopoietic disorders. In this editorial, we synthesize these advances and explore how emerging insights into hematopoietic aging mechanisms present opportunities for developing targeted therapeutic interventions against age-related hematopoietic decline and its clinical consequences. HSCs aging: The aging process in HSCs manifests through characteristic hallmarks including epigenetic dysregulation, genomic instability, metabolic rewiring, impaired proteostasis, loss of cellular polarity, and cellular senescence [Figure 1]. These interconnected alterations collectively drive stem cell exhaustion and functional decline, ultimately compromising hematopoietic output.[1] Emerging therapeutic strategies targeting these hallmarks offer promising avenues for HSC rejuvenation.Figure 1: Mechanisms underlying hematopoietic system aging. The aging of the hematopoietic system is driven by a complex interaction between intrinsic HSC alterations (represented by the pink section), changes in the bone marrow niche (represented by the light green rounded square surrounding the HSC), and extrinsic nonhematopoietic aging factors (located outside the green boundary). Black arrows indicate pathways or signals that lead to stronger impacts, while gray arrows represent weaker signals. Red upward arrows indicate increases, whereas green downward arrows indicate decreases. ↑: Up regulated; ↓: Down regulated; β3AR: β3-adrenergic receptor; AGEs: Advanced glycation end-products; CAR: CXCL12-abundant reticular cells; CXCL12: C-X-C motif chemokine ligand 12; EC: Endothelial cell; ECM: Extracellular matrix; HSC: Hematopoietic stem cell; IL-1: Interleukin-1; IL-6: Interleukin-6; MSC: Mesenchymal stromal cell; Ng2+/Nestin+ MSC: MSCs with high expression of neural/glial antigen 2 and nestin; NPY: neuropeptide Y; ROS: Reactive oxygen species; SASP: Senescence-associated secretory phenotype; SCF: Stem cell factor; SNS: Sympathetic nervous system; TNF-α: Tumor necrosis factor alpha.Key epigenetic alterations in aged HSCs include hypermethylation at differentiation-associated gene promoters coupled with hypomethylation at self-renewal loci. Additionally, chromatin accessibility increases at inflammatory enhancer regions containing binding motifs for transcription factors such as jun proto-oncogene (JUN), activating transcription factor (ATF)/signal transducer and activator of transcription (STAT), and interferon regulatory factor (IRF). Aging HSCs have persistent epigenetic memory, evidenced by incomplete transcriptional resetting even after transplantation into young microenvironments.[2] Notably, interventions targeting epigenetic regulators like PHD finger protein 6 (PHF6) can reverse age-related HSC impairments,[3] highlighting the potential for epigenetic therapies to restore balanced hematopoiesis in aging. The progressive genomic instability in aging HSCs is manifested through both DNA damage accumulation and telomere attrition. The increased DNA damage in aged HSCs stems from mechanisms including metabolic alterations, replication stress, and declining DNA damage response (DDR) efficiency, while telomere attrition activates innate immune responses mediated by cytosolic DNA sensors such as interferon gamma inducible protein 16 (IFI16). This process can be mitigated by telomeric DNA motif oligonucleotides such as A151,[4] suggesting promising therapeutic strategies to maintain genomic integrity in aging HSCs. The metabolic rewiring of HSCs during aging is characterized by a shift from glycolysis to oxidative phosphorylation (OXPHOS). This transition has profound consequences, particularly for mitochondrial function, including: (1) increased mitochondrial OXPHOS elevates reactive oxygen species (ROS) production while depleting oxidized nicotinamide adenine dinucleotide (NAD+) pools and reducing Sirtuin protein expression; (2) the resulting oxidative stress promotes genomic instability by inducing DNA damage and impairing repair mechanisms. The mammalian target of rapamycin (mTOR) pathway mediates the upregulation of mitochondrial OXPHOS, and although age-related mTOR hyperactivation drives excessive mitochondrial biogenesis and OXPHOS, mTOR inhibition helps maintain HSC quiescence and function.[5] Notably, mitochondrial membrane potential (MMP) serves as a robust biomarker of HSC aging, correlating with transcriptional and functional changes.[6] Therapeutic strategies targeting mitochondrial metabolism (e.g., nicotinamide riboside [NR]), mTOR activity (e.g., rapamycin), and MMP (e.g., mitoquinol/Mito-Q) show promise in mitigating HSC aging.[5–7] Impaired proteostasis in aging HSCs arises from a complex interplay of mechanisms. HSCs maintain protein quality through two key strategies, including limiting protein synthesis and deploying degradation systems such as autophagy and the ubiquitin-proteasome pathway. Notably, HSCs preferentially direct misfolded proteins to Bag3-dependent aggresomes for clearance via aggrephagy–a selective autophagy pathway–rather than proteasomal degradation.[8] This specialization makes HSCs highly susceptible to autophagy impairment, as they cannot fully compensate by upregulating proteasome activity, ultimately leading to protein aggregation and functional decline. Critical knowledge gaps remain regarding how these proteostasis networks collectively regulate HSC aging and whether they can be therapeutically targeted to rejuvenate aged HSCs. Asymmetric divisions balance self-renewal and differentiation in HSCs. However, aged HSCs exhibit a pronounced loss of polarity, shifting from asymmetric to predominantly symmetric divisions. This transition is accompanied by extensive changes in chromatin architecture and nuclear organization, such as a marked reduction in polarization of histone H4 lysine 16 acetylation (H4K16ac), due to the irregular distribution of Lamin A/C. This loss of polarity is associated with elevated activity of the small GTPase Cdc42, a transition from canonical to noncanonical Wnt signaling pathways, and significant alterations in DNA methylation and histone modification patterns.[9] Pharmacological inhibition of Cdc42 with Cdc42-activity-specific inhibitor (CASIN) restores polarity in aged HSCs and highlights Cdc42 and its upstream regulator Wnt5a as promising targets for interventions aimed at rejuvenating HSC function during aging.[9] The accumulation of senescent HSCs represents a critical aspect of hematopoietic aging. HSCs acquire senescent phenotypes via multiple interconnected pathways: (1) genomic instability from accumulated DNA damage; (2) chronic oxidative stress; (3) progressive telomere erosion; and (4) dysregulated oncogenic signaling—all exacerbated by age-related changes in both HSCs and their niche components. This transition is characterized by irreversible cell cycle arrest, development of a senescence-associated secretory phenotype (SASP), and expression of characteristic molecular markers including p53–p21 activation. Recent advances in senolytic therapies (such as BCL-2 family inhibitor ABT263)[10] and antibody-mediated depletion of senescent HSCs (such as myeloid-biased HSCs [my-HSCs])[11] demonstrate promising potential to restore balanced hematopoiesis and youthful immunity in aging contexts. To be noted, while recent advances have revealed multiple therapeutic targets, no single intervention fully reverses HSC aging. The most promising avenue lies in combination strategies that simultaneously address multiple hallmarks of aging—an approach currently underexplored. Niche aging in hematopoietic system: The aging process not only intrinsically impacts HSCs but also induces profound alterations in their BM microenvironment. These niche changes include vascular restructuring, cellular composition shifts, inflammaging, and extracellular matrix (ECM) remodeling, all of which collectively contribute to hematopoietic decline [Figure 1]. Targeting the aging BM niche serves as a promising therapeutic strategy to rejuvenate hematopoietic aging. Vascular restructuring in the aging BM is characterized by selective loss of arteriolar vessels and type H endothelial cells (ECs), whereas sinusoidal-type L vessels remain relatively preserved. This restructuring stems from impaired Notch signaling in aged ECs, which normally maintains endosteal niches by regulating arteriole formation. The decline in type H ECs reduces HIF-1α expression, exacerbating bone loss and diminishing pro-hematopoietic factors such as C-X-C motif chemokine ligand 12 (CXCL12) and stem cell factor (SCF). Importantly, young EC infusion can rejuvenate aged HSC function, highlighting the therapeutic potential of vascular niche modulation.[12] The aging BM undergoes significant remodeling of its cellular landscape.[1,13] For example, mesenchymal stromal cells (MSCs) are a multipotent progenitor crucial for supporting HSCs. Key MSC subsets, such as CXCL12-abundant reticular (CAR) cells and neuron-glial antigen 2 (Ng2)+ cells, decline in number and function, leading to reduced secretion of essential hematopoietic factors such as CXCL12, SCF, and interleukin (IL)-7, whereas megakaryocytes increase and become dysregulated. Aged MSCs increasingly exhibit adipogenic bias and develop a SASP. These changes create an inflammatory microenvironment that promotes myeloid bias and impairs lymphopoiesis. The aged hematopoietic niche develops a chronic low-grade inflammatory state known as “inflammaging”, characterized by elevated levels of pro-inflammatory cytokines including interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), and IL-1β.[1] Growing evidence implicates inflammation as a central driver of hematopoietic aging, as inflammatory exposure recapitulates key features of aged hematopoiesis at cellular, molecular, and clinical levels.[14] The antibody-mediated depletion of my-HSCs in aged mice restores youthful immune characteristics,[11] indicating my-HSCs as critical mediators of inflammaging. Although these results identify inflammation-directed interventions as a promising therapeutic avenue for hematopoietic rejuvenation, further studies are needed to explore the translational potential of rejuvenation approaches targeting inflammation directly in clinical settings. The ECM remodeling in the BM during aging includes reduced osteopontin expression, increased collagen crosslinking, dysregulated adhesion molecules expression, impaired growth factor dynamics due to decreased proteoglycan content, and accumulation of advanced glycation end-products. These alterations collectively create a pro-inflammatory niche that disrupts HSC maintenance. Of particular interest, the age-related decline in Netrin-1 contributes to microenvironmental genomic instability, whereas its restoration demonstrates therapeutic potential for HSC rejuvenation,[15] underscoring the promise of ECM-targeted interventions in aging. Nonhematopoietic systems influence hematopoietic aging: Beyond cell-intrinsic and niche-mediated aging mechanisms, hematopoietic decline is profoundly influenced by systemic factors that offer promising therapeutic targets [Figure 1]. Heterochronic parabiosis (HP) experiments demonstrate that exposure to a young circulatory environment can rejuvenate aged hematopoietic systems, restoring youthful gene expression profiles and cytokine-mediated interactions in hematopoietic stem and progenitor cells.[16] Age-related degeneration of the sympathetic nervous system impairs HSC maintenance through diminished β3-adrenergic and neuropeptide Y signaling; restoration of these pathways enhances DNA repair and antioxidant defenses, offering another avenue for rejuvenation.[17] Furthermore, the aging gut microbiome promotes myeloid bias through IL-1 signaling, which can be therapeutically targeted to restore balanced hematopoiesis.[18] Sex-specific aging patterns further complicate this picture, with estrogen loss in females and testosterone decline in males differentially impacting HSC function through distinct hormonal and epigenetic mechanism.[19,20] Notably, dysregulation of X-chromosome inactivation in aged HSCs reveals new targets for gene regulation therapies.[21] These connections not only deepen our understanding of hematopoietic aging but also provide multiple entry points for developing targeted rejuvenation strategies. Future therapies will need to address both the local BM environment and these broader physiological interactions to effectively combat age-related hematopoietic decline. Age-related hematological disorders and emerging therapies: Clonal hematopoiesis of indeterminate potential (CHIP), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML) represent a disease continuum driven by the stepwise accumulation of somatic mutations in aging HSCs. The inflammatory BM microenvironment serves as a critical catalyst across this spectrum. CHIP-associated clones promote inflammaging through nuclear factor kappa B (NF-κB) and IL-6 activation, which in turn fuels progression to MDS and AML. This mechanistic understanding has inspired therapeutic approaches targeting both malignant clones (hypomethylating agents, FMS-like tyrosine kinase 3 (FLT3)/ isocitrate dehydrogenase (IDH) inhibitors) and their inflammatory niche (Janus kinase (JAK)/IL-6 inhibition). Although multidrug chemotherapy and combination regimens remain the cornerstone for managing hematologic malignancies such as MDS and AML,[22] emerging immunotherapies and senolytics may offer particularly promising strategies for elderly patients by addressing the fundamental aging processes underlying this disease continuum.[23] Summary and prospects: Recent advances in hematopoietic aging research have revealed the complex interplay between intrinsic stem cell alterations, niche remodeling, and systemic factors that collectively drive hematopoietic decline. Despite this progress, fundamental gaps remain in our understanding of hematopoietic aging, including the hierarchical organization of aging mechanisms, reliable biomarkers and targets for hematopoietic aging and related disorders, and sex-specific differences in aging trajectories and their functional consequences. Given the limitations of current single-target approaches, the most promising therapeutic strategy involves developing interventions that simultaneously address multiple hallmarks of hematopoietic aging. The integration of artificial intelligence with single-cell-based multi-omics datasets may help decode the complex signaling networks governing hematopoietic aging and identify optimal combinatorial therapies. Ultimately, overcoming these challenges will require unprecedented collaboration between stem cell biologists, clinicians, and bioengineers to develop personalized approaches that maintain hematopoietic function throughout the human lifespan. Conflicts of interest None.
Source: Chinese Medical Journal
Authors: Lixiang Chen, Qiang Liu, Di Guan
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,000
OpenAlex ID: W4414564202