Clonal hematopoiesis of indeterminate potential (CHIP)—a pivotal contributor of aging and related disorders

Introduction

Hematopoiesis is the highly orchestrated process of blood production, which sustains the uninterrupted supply of functional blood cells over the lifespan of an organism. Hematopoiesis occurs through proliferation, commitment and differentiation of hematopoietic stem and progenitor cells (HSPCs) in the steady state or on the required demand of blood production under various external or internal factors. Hematopoietic stem cells (HSCs) give rise to most of the immune cell types and are a major source of blood production. Contribution of HSCs to the overall hematopoiesis is enhanced upon an increase in stress and inflammatory signals (1). Aging exposes HSCs to genotoxic stress and accumulation of DNA damage (2-4) and promoting clonal expansion HSCs (5). Clonal expansion during aging and is recognised as clonal hematopoiesis of indeterminate potential (CHIP) if the contribution of single mutant HSC clone to peripheral blood is more than 2 percent (6). CHIP is considered the premalignant state for hematological disorders with severity and risk factors of developing into blood cancer which is governed by the type of driver mutation present in the clones (7,8). Along with hematological disorders, CHIP is recognized as a major player in cardiovascular diseases (CVDs) (9), neurodegenerative diseases (10), autoimmune diseases (11) and other non-hematological disorders (12). Thus, understanding the mechanism and progression of clonal hematopoiesis (CH) holds immense potential to open a novel research avenue for developing therapeutic strategies to intervene and manage CHIP and CHIP-related disease occurrence.

CHIP

Hematopoiesis if the finely orchestrated process of formation of functional mature blood cells from HSCs. HSCs mainly reside in the long bones of adult mammals and regulate an intricate balance between quiescence, self-renewal and differentiation. HSCs differentiate into mature cell types of lymphoid, myeloid and erythroid lineage to supply functional blood cell types under intrinsic and extrinsic molecular signals (13,14). Bone marrow microenvironment (BMM), also called as HSC niche, surrounding the HSCs regulate HSC fate decisions through dynamic intercellular talk (15). Various intrinsic and extrinsic factors, including aging-associated alterations, contribute to the diminished functionality of normal HSCs, thereby shifting the balance of hematopoiesis toward HSCs harboring specific mutations that confer proliferative advantages to the affected cells. This phenomenon is referred to as CH.

CH was first identified as a non-random chromosome X-inactivation pattern in the myeloid compartment of a healthy women, which increased with age, suggesting an age-related clonal expansion. CHIP is defined as the presence of somatic pathogenic variants in leukaemia-associated driver oncogenes in HSPCs that confer a selective growth advantage, resulting in the clonal expansion of blood cells (16). These mutations are detected in peripheral blood at a variant allele frequency (VAF) of more than 2 percent, indicating that at least 2 percent of circulating blood cells originate from the mutated clone (17). Importantly, individuals with CHIP do not fulfil diagnostic criteria for hematologic malignancies. CHIP is therefore considered a pre-malignant but indeterminate state, reflecting early clonal evolution rather than overt disease (16).The mutations observed in CHIP predominantly affect genes involved in epigenetic regulation, chromatin remodelling, DNA damage response, and cytokine signalling, which are frequently mutated in myeloid malignancies (18). Large population-based sequencing studies suggest increased prevalence of CHIP rises age, affecting less than 1 percent of individuals under 40 years and approximately 10–20 percent of those over 70 years (8). CHIP is associated with increased risks of atherosclerotic CVD, hematologic malignancy, and all-cause mortality, likely driven by clonal inflammation and altered immune signalling (19). Further, age-related accumulation of somatic mutations, decline in DNA repair mechanisms, and changes in the BMM contribute to the emergence and expansion of CHIP clones (20). Understanding how CHIP contributes to disease development requires deeper insight into the molecular and epigenetic mechanisms that regulate HSC function and clonal expansion.

Epigenetic mutations in HSCs driving CHIP progression

Mutations in epigenetic regulators such as DNMT3A, ten-eleven translocation-2 (TET2), and additional sex combs-like 1 (ASXL1) primarily drive clonal expansion of mutant HSCs, resulting in CHIP. DNA methylation is a critical epigenetic modification regulating HSC differentiation and proliferation, and its dysregulation alters stem cell function.

DNMT3A

DNMT3A is the most frequently mutated gene in human HSCs during CH. Although DNMT3A and DNMT3B both function as de novo methyltransferases, DNMT3A loss has more profound effects than DNMT3B loss (21). Tight regulation of DNA methylation is essential for balancing HSC fate decisions (22). Altered methylation in Dnmt3a-mutant HSCs impairs differentiation and immortalizes HSCs (23). Dnmt3a loss upregulates stemness genes, suppresses differentiation pathways, and prevents shutdown of multipotency-associated signatures in HSCs (24). These epigenetic alterations predispose mice to MDS and T-ALL (25). DNMT3A mutations are common in myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). Conditional Dnmt3a knockout induces MDS/MPN with hepatomegaly and liver infiltration by mutant HSCs, highlighting its role in HSC tissue tropism through altered hematopoietic transcriptional programs (26).

The DNMT3A^R882H mutation induces focal CpG hypomethylation and active histone modifications, transactivating leukemogenic genes including Meis1, Mn1, and Hoxa clusters (27). Chronic mycobacterial infection or recombinant IFN-γ administration promotes expansion of Dnmt3a-mutant HSCs through altered methylation and reduced apoptosis (28). These mutant HSCs resist IFN-γ-induced apoptosis via hypomethylation of the Txnip locus, stabilizing p53 and increasing p21 expression (29). Recent studies showed that exogenous recombinant Dnmt3a protein lacking methyltransferase activity rescues mutant HSCs. These cells also exhibit sustained telomere length and enhanced telomerase activity, suggesting noncanonical functions of Dnmt3a in HSC regulation (30). Conversely, overexpression of Dnmt3a or Dnmt3L corrects hypomethylation in mutant cells (31). Aging-associated tumor necrosis factor-alpha (TNF-α) signaling selectively promotes Dnmt3a-mutant HSC expansion, which is abolished by TNFR1 deletion, further implicating inflammatory cytokines in clonal expansion (32). Similar therapeutic approaches are being explored to limit DNMT3A-mutant clone expansion and CHIP progression. Dnmt3a/Tet2 double-knockout mice display cooperative epigenetic effects with upregulation of Klf1 and Epor and accelerated malignancy, highlighting Tet2-mediated regulation of hematopoietic differentiation and transformation in the presence of Dnmt3a mutations (33).

TET2

Tet2 is an α-ketoglutarate-, iron-, and oxygen-dependent dioxygenase that converts 5-methylcytosine to 5-hydroxymethylcytosine, thereby promoting active transcription. Tet2 is considered a master epigenetic regulator of hematopoietic cells (34). Tet2 exhibits antagonistic activity to Dnmt3a during hematologic malignancies (23).

Tet2 deficiency reduces genomic 5hmC levels, alters HSC self-renewal and differentiation, and expands the HSPC pool (35). Tet2-mutant HSCs exhaust at rates similar to normal HSCs but skew committed progenitors toward myeloid differentiation (36). Tet2-associated CH is predominantly myeloid-biased with expansion of myeloid progenitors, whereas Dnmt3a-associated CH is driven by multipotent progenitors (34,37). Tet2 deletion decreases 5hmC and increases 5mC levels in BM cells, enhancing HSC activity, myeloid bias, and progression to myeloid malignancies (38). Similarly, Tet2-mutant HSCs exhibit enhanced self-renewal and significant HSC pool expansion (39,40).

Azacitidine and ascorbate restore 5hmC signatures in Tet2-mutant HSCs (41), while ascorbate suppresses leukemogenesis (42). Tet2-mutant leukemic stem cells accumulate 5mC modifications on TSPAN13 mRNA, stabilizing it and promoting self-renewal and BM homing via CXCR4/CXCL12 signaling (43). Aging enhances Tet2-mutant clonal expansion through TORC1, p53, and RUNX1 signaling, altering ribosome biogenesis and mitochondrial fitness (44). Tet2 loss also enhances HSC function and self-renewal under altered oxygen tension (45), similar to hypoxic conditions during leukemogenesis (46).

Chronic inflammation promotes Tet2-mutant clone expansion through cGAS-STING signaling, whereas STING inhibition suppresses aberrant proliferation of Tet2-mutant leukemic cells (47). During normal aging, Tet2 regulates spatial distribution of H3K9me3-marked heterochromatin, and Tet2 deletion in aged HSCs rescues age-associated defects (48), underscoring its role in aging-associated HSC function. Single-base methylome analysis revealed Tet2 mutation-associated promoter hypermethylation and repression of IFG1, promoting HSC expansion and CH (49). Tet2-mutant HSCs also resist IL1B-mediated DNA methylation and HSC exhaustion (50). Thus, mechanistic studies of Tet2-mediated HSC regulation are opening new therapeutic avenues for leukemogenesis and CH.

ASXL1

ASXL1 is among the most common mutations in myeloid malignancies and CHIP. It functions as a core subunit of the RNA polymerase-II complex (51). ASXL1 loss reduces HSC pool size and function and induces MDS-like disease in mice due to global reduction in H3K27me3 and H3K4me3 levels (52). ASXL1 regulates key histone modifications including H2AK119Ub, H3K4me3, and H3K27me3. Consequently, ASXL1 mutations cause aberrant gene expression and drive myeloid malignancies. ASXL1 interacts with PRC1 and PRC2 complexes to regulate monoubiquitination and trimethylation, respectively, thereby modulating gene expression (53).

HSCs expressing C-terminal truncated ASXL1 exhibit aberrant proliferation and dysfunction. In young mice, ASXL1 mutation promotes BAP1-mediated deubiquitination and hyperactivates AKT/mTOR signaling, causing DNA damage-associated HSC dysfunction, whereas in aged mice it confers fitness advantage over normal HSCs (54). In vitro ASXL1 knockdown induces apoptosis and G0/G1 arrest in CD34⁺ cord blood HSCs. Loss of H3K2me3 occurs in erythroid progenitors, whereas myeloid progenitors remain relatively resistant (55). Similarly, ASXL1-knockout mice develop MDS/MPN-like disease with defective erythroid maturation associated with altered erythroid gene expression, increased apoptosis, and reduced H3K27me3 and H3K4me3 levels (56).

Like DNMT3A-mutant HSCs, ASXL1-mutant BM cells transplanted into mice exhibit elevated interleukin (IL)-6 and IL-1β levels, enhancing inflammation-driven CH (57). Expression of C-terminal truncated ASXL1 reduces H3K4me3 and H2AK119Ub without affecting H3K27me3, conferring competitive advantage and increased leukemogenic susceptibility to mutant HSCs (58). ASXL1^G643Fl/+ knock-in mice exhibit reduced H2AK119Ub at the p16Ink4a promoter, impairing hematopoiesis through aberrant PRC1-mediated histone modification (59). Dual ASXL1 and CSF3R mutations promote myeloid-biased HSC expansion, with CSF3R mutation restoring H2AK119Ub in ASXL1-mutant cells, highlighting context-dependent ASXL1 function in HSC regulation (60). ASXL1 deletion in BM MSCs also reduces expression of HSC maintenance genes through dysregulated transcription, impairing HSC support functions (51).

Other genes driving CHIP

JAK-STAT pathway mutations are strongly associated with CHIP. JAK2V617F is a major driver mutation in MPNs and a well-established thromboembolic risk factor. The association between JAK2-CHIP and microthromboembolism-related events in the general population remains under investigation (61). CHIP-associated activation of JAK-STAT signaling increases thrombotic and cardiovascular risk (62). Other important CHIP-associated genes include TP53, PPM1D, SF3B1, SRSF2, and IDH1/2, particularly in therapy-related or high-risk CHIP (63). These mutations confer competitive fitness advantages under aging, inflammatory, and genotoxic stress conditions and determine the risk association with various diseases.

CHIP as a risk factor for diseases

CHIP is a recognised as a precursor state for myeloid neoplasms, including AML, MDS, and MPN (16). Although the absolute risk of transformation is low, the relative risk of developing hematologic cancer is significantly higher compared to individuals without CHIP. Risk factor varies depending on the specific gene mutations. Long-term follow-up studies demonstrate that CHIP confers an approximately 0.5–1% annual risk of progression to myeloid malignancies due to the acquisition of additional driver mutations, clonal evolution, and genomic instability (64). Clone size plays a critical role in CHIP, as larger clones are associated with higher risks of adverse outcomes and progression to myeloid malignancies (65). The presence of multiple somatic mutations in CHIP is associated with greater clonal complexity, larger clone sizes, higher risk with increased inflammatory signalling and a greater likelihood of developing atherosclerotic CVD and progression to myeloid malignancies such as MDS or AML (66). These findings suggest that both the number and type of mutations are important determinants of clinical risk in CHIP. Growing evidence connecting CHIP with systemic disease arises from complementary epidemiological, experimental, and translational investigations (67,68).

CHIP is also associated with increased systemic inflammation and is an independent risk factor for CVD, including coronary artery disease, myocardial infarction, atherosclerosis, and worse outcomes in heart failure. It is also linked to higher risks of stroke, pulmonary embolism, chronic kidney disease, chronic obstructive pulmonary disease (COPD), metabolic disturbances, obesity, liver disease, and increased all-cause mortality (64,69). Overall, CHIP represents an important and independent risk factor for both CVD and mortality, particularly in older populations. Large-scale sequencing analyses from longitudinal cohorts demonstrate that individuals carrying CHIP mutations exhibited approximately double the risk of coronary heart disease, particularly elevated in clones harboring TET2 or JAK2 mutations (70). Mechanistically, mutations—particularly in TET2 (71) and DNMT3A—enhance the production of pro-inflammatory cytokines by mutant myeloid cells, thereby accelerating vascular inflammation and plaque formation (72). Loss of TET2 in hematopoietic cells accelerated atherosclerosis despite normal lipid levels due to increased macrophage inflammasome activation and heightened vascular inflammation. Individuals with JAK2 mutations show markedly elevated thrombotic risk, including ischemic stroke and venous thrombosis due to increased neutrophil extracellular trap (NET) formation and platelet activation (71,73).

CHIP is also associated with an increased risk of cerebrovascular events, especially ischemic stroke (74). CHIP is associated with hypercoagulability, endothelial dysfunction, and an increased thrombotic tendency (75). Chronic inflammation driven by CHIP clones further contributes to vascular injury and cerebrovascular pathology.

CHIP has been implicated in several non-malignant inflammatory conditions like Rheumatoid arthritis (76), vasculitis and chronic inflammatory states (77). Mutant myeloid cells derived from CHIP clones exhibit heightened inflammatory responses, creating a feedback loop that sustains clonal expansion and exacerbates systemic inflammation (78). This highlights CHIP as a bridge between aging, immune dysfunction, and chronic diseases.

CHIP has particular relevance for individuals exposed to chemotherapy or radiation therapy (79,80). Treatment-related DNA damage creates selective pressure that favours the expansion of clones with mutations in TP53 and PPM1D, which confer resistance to apoptosis (81). These clones can persist and expand over time, significantly increasing the risk of therapy-related myeloid neoplasms (t-MNs), which are often aggressive and carry a poor prognosis. In many cases, CHIP mutations are detectable years before the development of overt t-MNs (82,83). Thus, CHIP is emerging as a major risk factor with its proven association with various aging related diseases (Table 1). Further, age-associated alterations in HSCs not only drive clonal expansion in CHIP but also contribute to progressive changes in immune system function during aging.

CHIP during aging and its effect on the immune system

Aging is the strongest determinant of CHIP. With advancing age, HSCs accumulate somatic mutations due to lifelong replication stress, declining DNA repair capacity, telomere attrition, and chronic exposure to inflammatory and environmental insults (83). Certain mutations—particularly in DNMT3A, TET2, ASXL1, and JAK2—confer a competitive advantage that promotes clonal expansion (17). Over time, these mutant clones progressively dominate hematopoiesis, leading to a skewed production of immune cells derived from altered progenitors. The aging BMM further favors these clones by providing selective advantage for clonal expansion (19). Mutations in genes such as TET2 and DNMT3A reprogram myeloid cells toward a hyperinflammatory phenotype (71). CHIP-derived macrophages exhibit increased activation of inflammatory pathways, including the NLRP3 inflammasome, resulting in excessive production of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α (94,95). These exaggerated responses are disproportionate to immune stimuli and persist even in the absence of acute infection. Consequently, innate immune cells contribute to sustained tissue inflammation, endothelial dysfunction, and immune-mediated organ damage commonly observed in older individuals (77). In addition to innate immune dysregulation, CHIP also affects adaptive immune function. There is an alteration in T-cell homeostasis in individuals carrying CHIP mutations, characterised by reduced naïve T-cell pools, impaired clonal diversity, and functional exhaustion (96). Inflammation caused by CHIP interferes with efficient antigen presentation and Priming of T cells, leads to suboptimal immune surveillance against malignant or infected cells (97). Regulatory T-cell balance is also disrupted, further contributing to immune dysregulation (98). All together, these changes weaken adaptive immune responses and weaken the capacity to mount effective, targeted immunity.

CHIP is progressively acknowledged as a key driver of inflammaging, an aging characteristic described by persistent, low-grade systemic inflammation (99). Inflammatory mediators are continuously released by mutant myeloid cells, creating a self-perpetuating inflammatory loop. This chronic inflammatory state contributes to the development of multiple age-related diseases, including CVD (72), neurodegeneration and metabolic dysfunction. Moreover, infection susceptibility and vaccine efficacy in the elderly are dependent on immune dysregulation associated with CHIP, which has clinical implications (100). Pathogen clearance is delayed due to impaired innate responses, while long-term immune memory is compromised due to dysfunctional adaptive immunity. As a result, individuals with CHIP are more susceptible to severe infections and demonstrate diminished response to the vaccines, including those targeting influenza and other respiratory pathogens (101). Chronic inflammation further interferes with the effectiveness of the vaccine-induced immunity, emphasising CHIP as a potential contributor to poor immune resistance in aging populations (102) proving aging as a major contributor to CHIP progression.

Mechanisms driving CHIP during aging

During aging, DNA repair pathways become defective, allowing mutations to accumulate and expand (103). Other factors, such as environmental exposures, endogenous genotoxic stress, and chronic inflammation, further accelerates mutational burden (104). Most of the acquired mutations are neutral or deleterious; a subset of clones containing gene mutations enhances HSC survival or self-renewal, forming the molecular basis of CHIP (105,106). CHIP mutations associated with driver genes provide a competitive advantage that allows mutant HSCs to outcompete normal counterparts (107). Mutations in epigenetic regulators such as DNMT3A, TET2, and ASXL1 alter chromatin accessibility and transcriptional programs, enhancing self-renewal and resistance to differentiation (39). These epigenetic changes enable perpetual clonal expansion without any immediate malignant transformation (108). In particular, DNMT3A mutations enhance stem cell persistence, while TET2 loss promotes inflammatory signalling that reinforces clonal fitness, especially under stress conditions common in aging BM (109). DNA damage response pathways are altered with aging that plays a critical role in CHIP development. There is an Increased levels of oxidative stress in aging HSCs, which generate reactive oxygen species (ROS) that cause DNA base modifications, strand breaks, and genomic instability (110). Concurrently, replication stress arising from shortened telomeres and altered cell cycle regulation further compromises genome integrity (111). Mutations such as TP53 and PPM1D affecting DNA damage (112) response genes allow damaged cells to evade apoptosis and persist, thereby expanding under conditions where normal HSCs undergo attrition (80).

Aged HSCs display prominent hallmarks of stem cell aging including increased the depth of quiescence, reduced self-renewal property, changes in their cell fate propensities and reduced heterogeneity with decreased functionality (113). HSC aging is controlled by intrinsic aging drivers like increased myeloid gene activation, accumulation of DNA damage, loss of cell polarity and reduced autophagy (114) along with dynamic changes in the BMM (115). The occurrence of myelo-proliferative disorders and anemia is highly associated with aging related changes in the hematopoietic system. Increased myeloid cell frequency and decreased lymphoid cell production is another characteristic phenomenon of aged hematopoiesis (116-118). The preferential myeloid cell production is result of time-dependent accumulation of myeloid-biased HSCs (Mye-HSCs) and exhaustion of lymphoid-biased HSCs during aging (119,120). Increased proinflammatory signalling in the BM microenvironmental is a major aging-induced extrinsic alteration. This age-induced inflammation-like milue is termed as ‘inflammaging’ (121). DNA damage accumulation, dysfunctional immune response, increased pro-inflammatory molecules, senescent cell accumulation, defective autophagy and activation of transcription factors associated with inflammatory signalling are the main drivers of inflammaging (79).

Dynamic properties of the BMM also change during aging. These changes also affect the normal HSC functionality. Aging of BMM is associated with decreased bone resorption activity, increased adipocytes, altered extracellular matrix components and decreased expression of HSC-supportive cytokines (122-125). The frequency and proliferative potential of mesenchymal stromal cells (MSCs) decrease while senescence levels increase with age in BM (126). Genomic DNA aberrations, reduced telomere length, and increased ROS is characteristics of aged MSCs. The aged MSCs are also skewed towards adipogenic lineage (130,131) and negatively regulate HSC self-renewal and functionality (132). The frequencies of niche endothelial cells (ECs), PDGFR-β⁺ perivascular cells, the important regulators of HSC functionality in BM niche are decreased during aging (133-135), resulting in dysregulated hematopoietic activity.

On the other hand, the BMM functions as a complex ecological system in which HSCs compete for resources such as limited space, nutrients, and growth factors (136). The expression of pro-inflammatory cytokines such as TNF-α, IL6 (137), TGF-β1 (138), IFN-γ and RANTES (139) is increased and HSC-supportive cytokines such as VEGF, IGF, EGF and G-CSF (129) is decreased in aged BMM along with significant alteration in the stromal support, vascular integrity, and cytokine signalling (140). Mutant HSCs survive under these altered conditions, gradually displacing normal HSCs. This process of clonal competition leads to the dominance of specific CHIP clones, reflecting Darwinian selection within the hematopoietic ecosystem rather than random expansion (141). Chronic inflammation is both a cause and a consequence of CHIP (71). The levels of inflammatory cytokines such as IL-6, TNF-α, and IL-1β are elevated in aging individuals, creating a selective environment that favours mutation-bearing clones (94). HSCs harbouring mutations in genes like TET2 and DNMT3A display heightened resistance to inflammatory stress and may even exploit inflammatory signalling to enhance proliferation (77). This creates a self-reinforcing loop in which inflammation promotes clonal expansion, and expanded clones further amplify inflammatory signalling (122). Aging is associated with profound metabolic reprogramming of HSCs, including altered mitochondrial function, reduced autophagy, and changes in glycolytic and oxidative phosphorylation pathways (142). These metabolic shifts impair the function of normal HSCs while providing a relative advantage to mutation-bearing clones that can better adapt to metabolic stress (143). CHIP-associated mutations may enhance metabolic flexibility, allowing mutant HSCs to maintain energy homeostasis and survive in nutrient-limited or hypoxic niches (144). Thus, drastic changes in the BMM during aging and metabolic remodelling of HSCs emerges as a key contributor to clonal dominance during aging (145).

Role of the bone marrow microenvironment in CHIP

Though evolution and proliferation of the mutant CHIP clones is dependent on the intrinsic factors and mutations they carry, the survival and the fate decisions of the clones highly rely on the BMM. BMM changes largely govern the proliferation and clonal expansion during CHIP progression (146). BM from CHIP bearing individuals exhibit highly remodelled BMM with increased proinflammatory cytokine levels in hematopoietic as well as stromal cell populations along with changes in the cell cycle and interferon related genes. Immune cell alterations are observed in the BM from during CHIP progression with increased frequency of T cells and decreased frequency of B cells with myeloid prominent myeloid skewing. Interestingly the stromal cells from the CHIP BM induces the non-cell-autonomous effects on the transplanted WT cells, confirming that the microenvironmental alterations during CHIP progression promotes the proliferation and expansion of mutant clones (146). The niche compartmentalization and spatial differences in the BM are also promote specific clone proliferations. The rigorous clonal cell expansion was seen to be restricted in the zone of continuous active bone remodelling. Inhibition of bone resorption activity reduces the clonal expansion of Tet2 mutant HSPCs sparing the WT counterparts. These clones were observed to be proliferating in the close vicinity of CD206⁺ tissue resident macrophages, which act as the immunosuppressive shields for the mutant clones (147). Infection associated inflammatory signalling is enough to drive CH in Dnmt3a^−/− mice. Further, single injection of interferon-gamma (IFN-γ) induces CHIP like phenotypic changes and induce expansion of clones in these mice, confirming the effect of external inflammation inducing factor on progression of CH. Dnmt3a mutants also show blunt response to the induced inflammation and enhance their self-renewal upon infection induced inflammatory signalling (28). In another study, transplantation of Dnmt3a mutant cells in normal wild type recepients induce scenesence related gene expression profile and increased p16, p21 and β-galactosidase gene expression in Osteo-CAR and Adipo-CAR populations of the wild type BM stromal cells. Parallelly, increased expression of anti-apototic proteins BCL-2 and BCL-xL was observed in the BM stromal cells when they were co-cultured with Dnmt3a mutant HSPCs (148).

BMM undergoes inflammatory remodelling during CH and further develops into MDS. Reduction in CXCL12⁺ adipogenic stromal cells occurs and emergence of noval and exclusive inflammatory mesenchymal stromal cells (iMSC) which marks the initiation of clonal hematopoisis supporting BM niche remodelling. The crosstalk between iMSCs and IFN-responsive T-cells initiate further inflammation in the BM niche to promote clonal expansion (149). Adipocytes known to inhibit normal hematopoiesis by reducing HSC self-renewal and proliferation (150). Contrarily, obesity associated fatty BM induces CH by activating proinflammatory gene expressions and supports clonal expansion of Tet2^−/− HSPC clones (151). Moreover, Fatty BM induces aberrant proliferation of DNMT3A mutant HSCs via increase in IL-6 levels and increased inflammatory signalling in the BMM (152). Tet2 inactivating mutation is associated with increased TNF-α gives selective advantage for Tet2 mutant BM cells proliferation. This happens due to reduction in apoptosis levels without altering their colony forming ability (153). Further, aging associated Tet2^+/− CH acts through IL-1/IL-1R receptor axis and inhibition of this axis impairs the clonal expansion of Tet2^+/− cells (154). Studies using on aged BMM using aged recipient mice for the transplantation experiments shows significant higher reconstitution of DNMT3A mutant BM cells in aged mice compared to young counterparts. Surprisingly, analysis of BM compartment exhibited reduced DNMT3A mutant HSCs in the BM of aged mice, indicating clonal expansion occurs down the differentiation arm in progenitors and not at the HSC level. The observed clonal expansion was also associated with the increased TNF-α levels in the aged BM compartment (155). Thus, BMM remodelling is emerging as the significant contributor of CH.

Diagnostic tools for CHIP

The diagnosis of CHIP primarily depends on next-generation sequencing (NGS) technologies that enable the detection of low-frequency somatic mutations in peripheral blood (17,69). NGS offers high sensitivity and resolution, allowing identification of age-related clonal mutations in individuals without overt hematologic disease (18). Whole-exome sequencing (WES) also captures coding regions across the genome and has been instrumental in the initial discovery of CHIP (156). WES allows unbiased detection of somatic mutations in known and novel genes involved in CH (103). However, its relatively lower sequencing depth compared to targeted approaches limits sensitivity for detecting low VAF mutations (63). Consequently, WES is primarily used in research settings rather than routine clinical diagnostics.

Targeted NGS panels focusing on recurrently mutated myeloid malignancy-associated genes are the most widely used diagnostic tools for CHIP in clinical and translational settings (81). These panels typically include genes such as DNMT3A, TET2, ASXL1, JAK2, TP53, PPM1D, and spliceosome genes, and allow deep sequencing with high coverage (100). This approach enables reliable detection of small clones and provides clinically relevant information regarding mutation type, burden, and associated risk (6). VAF is also a key parameter in CHIP diagnosis and risk stratification (6). Lower VAFs may represent emerging or transient clones, while higher VAFs indicate more substantial clonal expansion and are associated with increased risk of progression to myeloid neoplasms and non-malignant complications such as CVD (20). Accurate identification of CHIP requires robust bioinformatics pipelines capable of distinguishing true somatic mutations from sequencing artifacts and germline variants (157). Standard workflows include read alignment, variant calling, filtering, and annotation using tools such as Mutect2, VarScan2, Strelka, and GATK pipelines (158). Matched germline controls, error-corrected sequencing, and molecular barcoding further improve sensitivity and specificity, particularly for low-frequency variants. Functional annotation and pathogenicity prediction are essential for determining the clinical relevance of detected mutations (159).

Currently, routine population screening for CHIP is not recommended, as consensus clinical guidelines are still evolving (83). CHIP is often detected incidentally during genomic testing performed for other indications, such as cancer sequencing or evaluation of cytopenias (160). Limitations include uncertainty in predicting individual disease risk, psychological burden associated with incidental findings, and lack of standardized management strategies. Ethical considerations surrounding disclosure, follow-up, and intervention remain areas of active debate (79).

Accurate diagnosis requires differentiation of CHIP from related but clinically distinct conditions like clonal cytopenia of undetermined significance (CCUS), MDS and clonal cytopenias. Presence of CHIP-associated mutations accompanied by persistent unexplained cytopenias, with a significantly higher risk of progression to MDS (161). Integration of clinical features, blood counts, BM morphology, cytogenetics, and molecular findings is essential for accurate classification and risk assessment (162), thereby enabling the identification of patients who may benefit from CHIP-related therapeutic strategies aimed at mitigating disease progression and associated complications

Available treatments for CHIP and related diseases

At present, there is no approved targeted therapy specifically for CHIP (79). Given the absence of overt hematologic malignancy or cytopenias, management primarily consists of clinical monitoring and risk stratification (6). Longitudinal follow-up with periodic blood counts and molecular assessment may be considered, particularly in individuals with high-risk mutations (e.g., TP53, JAK2) or high VAFs. Current consensus emphasizes avoiding overtreatment while identifying individuals at increased risk for disease progression (79).

CHIP is an independent risk factor for atherosclerotic CVD, heart failure, and stroke, largely mediated through chronic inflammation (83). Management focuses on aggressive control of traditional cardiovascular risk factors, including dyslipidemia, hypertension, and diabetes (71). Statins may provide dual benefits by lowering lipid levels and attenuating inflammatory signaling (160). Anti-inflammatory agents targeting cytokine pathways implicated in CHIP-associated atherogenesis are under active investigation, although routine use is not yet recommended (163). Individuals harboring JAK2 V617F mutations exhibit an increased risk of venous and arterial thrombosis, even in the absence of overt MPN (164). In selected high-risk patients, antithrombotic strategies such as low-dose aspirin may be considered on a case-by-case basis, particularly when additional thrombotic risk factors are present (75). However, standardized guidelines for prophylactic anticoagulation in CHIP are lacking, and decisions must balance thrombotic and bleeding risks (160). If CHIP progresses to MDS or AML, established disease-specific protocols are recommended to be followed (165). These may include hypomethylating agents, intensive chemotherapy, targeted therapies (e.g., FLT3 or IDH inhibitors), or allogeneic HSC transplantation depending on patient age, comorbidities, and molecular risk profile (166). Early identification of high-risk CHIP clones may enable closer surveillance and timely intervention (109).

Preclinical and clinical studies have highlighted IL-1β, IL-6, and NLRP3 inflammasome pathways as central mediators of CHIP-associated inflammation (163). IL-1β inhibition has shown cardiovascular benefit in patients with CH, suggesting a potential therapeutic avenue (94). NLRP3 inhibitors are currently in early-phase trials and represent a promising strategy to mitigate systemic inflammation driven by mutant myeloid cells (167). Given the central role of epigenetic regulators such as DNMT3A and TET2 in CHIP, epigenetic therapies are being explored. Hypomethylating agents and other chromatin-modifying drugs may theoretically counteract aberrant self-renewal and differentiation of mutant HSCs, although their use in asymptomatic CHIP remains experimental and currently unjustified outside clinical trails (39,168). Gene-editing technologies, including CRISPR-Cas9-based approaches (169), are under investigation for correcting pathogenic mutations in HSCs (170,171). While still at a conceptual and preclinical stage, these strategies offer long-term potential for preventing clonal expansion and disease progression, particularly in high-risk individuals (172).

Non-pharmacological strategies may play a supportive role in mitigating CHIP-associated risks (173). Regular physical activity, smoking cessation, weight management, and anti-inflammatory dietary patterns have been associated with reduced systemic inflammation and improved cardiovascular health (174). While direct evidence linking lifestyle interventions to reduced CHIP clone expansion is limited, these measures are widely recommended due to their overall health benefits and low risk (175).

Global research and medical status on CHIP

The socio-economic burden associated with the management of aging-related diseases presents a significant challenge for the global economy. Proven association and implication of CHIP in numerous haematological, cardiovascular and neurological diseases makes CHIP centric research as major area of scientific and economical interest for its risk predictive ability and probable nexus for the development of intervening therapies to manage these diseases. Recent records for last one decade shows the overall gradual and significant increase studies aimed to understand the mechanism of CHIP development and concomitant increase in the number of CHIP related research publications. The United States of America (USA) is at the forefront of leading the research related to CHIP with more that 50 percent high impact research publications coming out from the USA. CHIP has been the major area of research for most of the globally accredited research institutes and Harvard Medical School which publishied the most CHIP related peer-reviewed research articles in the recent years. American Society of Hematology’s research journal—Blood, has published numerous CHIP-related studies in the last decade. The global research interest is currently invested in understanding the association of the specific CHIP mutation with development of CHIP into AML and CVDs (176).

Understanding the dynamics, kinetics and intricate mechanisms of development of CHIP and expansion of the clones has been another recent focus of longitudinal studies in specific cohorts. Fabre et al., tracked the cohort of 385 subjects with 55 years and older individuals for 13 years. These individuals bared 697 CHIP clones which gradually expanded over the time. The rate of clonal expansion for each clone type was mainly driven by the type of mutation it inherited. DNMT3A and TP53 mutant clones expanded at the average rate of 5 percent expansion per year while aggressive mutation of SRSF^p95h clones expanded at the average rate of 50 percent per year. Additional detailed analysis revealed that the expansion of the DNMT3A clones occurs in the earlier phase of aging and splicing gene related mutation baring clones taking over the expansion process in the later stage of CH. Interestingly, TET-2 mutant clones expansion was gradual and continued gradually for the overall process of CH (177). In another study, clonal analysis of blood from individuals over 75 years of age showed that most of the blood production was restricted to 12–18 independent lone types. This clonal expansion was found to be started at approximately 40 years of age with only one fifth of the clones linked to the known driver mutations (178). Study on two different cohorts which included 500 subjects in one and 1,091 subjects in another from the age group of 70–90 years old confirmed that the clonal fitness associated with inherent mutation strongly outweighs other biological differences in the individuals and underscores the potential for development of personalized clinical interventions for CHIP management (179). A cohort based study in 6,976 women from post-menopausal group tracked for 16 years exhibited the impact of telomer length, germline mutations in the clones and IL-6 signalling on the overall clonal expansion. The clonal expansion kinetics in this cohort established the strong corelation between CHIP and leukemia, cytopenia and all-cause mortality (180). Overall, the well-designed longitudinal studies comprising of various cohorts and large number of subjects involved along with accumulating scientific evidence recognize CHIP as major age-related risk factor for the global population.

Conclusions

Considering the pivotal role of CHIP related mutations and clonal expansion in a huge spectrum of disease manifestation, CHIP related diagnostics and intervention therapies can evolve as a better disease prediction and management strategy in near future. Currently, a major unmet need in the field of CH is the development of standardized screening guidelines for CHIP determination (16). Currently, CHIP is most often identified incidentally, and there is no consensus on who should be tested, at what age, or using which sequencing platforms (86). Future efforts must focus on validated risk-stratification models that integrate genetic factors including mutation type, number, VAF, age, comorbidities and laboratory parameters to distinguish low-risk individuals from those requiring closer surveillance (63). The absence of CHIP-specific therapies highlights the need for targeted interventions that either reduce clonal burden or mitigate downstream pathological effects, particularly inflammation (83). Future drug development may focus on selectively modulating mutant HSPCs or attenuating their pro-inflammatory signalling without impairing normal hematopoiesis (94). Such approaches could shift CHIP management from passive monitoring to active risk reduction (181).

Large-scale longitudinal cohort studies are essential to better define the natural history of CHIP (182). While CHIP is associated with an increased risk of myeloid malignancies, the absolute risk for most individuals remains low (20). Long-term follow-up studies with serial molecular profiling will help identify patterns of clonal expansion, acquisition of secondary mutations, and triggers for malignant transformation, enabling earlier and more precise intervention strategies (105). Given the strong and independent association between CHIP and CVD, future research should aim to incorporate CHIP status into cardiovascular risk prediction algorithms (69). Integrating molecular data with traditional risk factors could improve prediction accuracy and guide personalized preventive strategies, particularly in individuals with high-risk mutations such as TET2 or JAK2 (160,183). Single-layer genomic analyses provide an incomplete picture of CHIP biology (184). Future studies leveraging multi-omics approaches, including epigenomics, transcriptomics, proteomics, and metabolomics, will be critical for understanding clonal behavior, functional heterogeneity, and interaction with systemic aging processes (185). Such integrative analyses may uncover novel biomarkers and therapeutic targets (141).

Emerging evidence suggests that the aging BMM plays a key role in shaping clonal selection and expansion (136). Future research should explore microenvironment-targeted interventions, including modulation of inflammatory cytokines, stromal cell function, and metabolic niches, as potential strategies to suppress the competitive advantage of mutant clones (123). Ultimately, the future of CHIP management lies in personalized medicine. Individualized assessment based on genetic profile, clonal dynamics, inflammatory status, and comorbid conditions could guide tailored surveillance and intervention strategies (8). Such frameworks would allow clinicians to balance the risks of overtreatment against the benefits of early prevention, aligning CHIP care with precision medicine principles (17,100).

Future research in CHIP must move beyond association studies toward mechanism-driven, clinically actionable strategies. Advances in risk prediction, targeted therapy development, and systems-level biology are expected to transform CHIP from an incidental genomic finding into a modifiable risk factor for aging-related diseases (Figure 1).

Figure 1 CHIP: a link between aging, immune dysregulation, and chronic disease. The figure summarises how aging-associated somatic mutations in HSCs lead to clonal hematopoiesis, systemic inflammation, and multi-organ disease, thereby positioning CHIP as a key mechanistic link between aging, immune dysregulation, and chronic disease. Created in BioRender. Gowda N. [2026] https://BioRender.com/1uvn14m. BM, bone marrow; NGS, next-generation sequencing; WES, whole-exome sequencing; CHIP- clonal hematopoiesis of indeterminate potential; HSCs, hematopoietic stem cells.

Acknowledgments

The authors would like to thank the Editors of Annals of Translational Medicine for extending this opportunity. They would also like to thank Dr. Anushree Kogje for fact-checking and editing support, and Dr. Naveen Gowda for his help in creating the figure using BioRender. The authors thank the SKAN Research Trust, India, for providing institutional support and access to office facilities, internet connectivity, and computational resources used in the preparation of this manuscript.

Footnote

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-2026-1-0030/prf

Funding: This work was supported by the SKAN Research Trust, India.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-2026-1-0030/coif). R.K. serves as an unpaid editorial board member of Annals of Translational Medicine from May 2025 to June 2027. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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