Clinical Epigenetics最新文献

{"title":"Exploring a targeted epigenetic clock based on mortality-associated CpGs as a potential biomarker for frailty.","authors":"Jonathan Awuah, Dhayana Dallmeier, Felix Boehm, Laura Herdtle, Dietrich Rothenbacher, Juan-Felipe Perez-Correa, Wolfgang Wagner","doi":"10.1186/s13148-026-02196-9","DOIUrl":"10.1186/s13148-026-02196-9","url":null,"abstract":"<p><strong>Background: </strong>Age-related DNA methylation changes are promising biomarkers to track the individual aging process. Particularly second-generation epigenetic clocks capture aspects of biological age more accurately, but the requirement of genome wide profiles hampers implementation into practice. We therefore aimed to develop a simplified, targeted approach based on individual age- and mortality-associated CpG sites measurable by digital PCR.</p><p><strong>Results: </strong>We selected three CpG sites strongly associated with all-cause mortality in the Lothian Birth Cohorts and with chronological age in multiple publicly available repositories to establish the targeted age- and mortality-associated epigenetic clock (TaM clock). For comparison, we applied a previously published three-CpG signature selected solely for correlation with chronological age (TaC clock). These signatures were initially benchmarked using DNA methylation profiles from 20 frail and 20 non-frail participants of the ActiFE cohort. In fact, in this subset the TaM clock revealed significant association between the delta age and the frailty status based on a 32-item frailty index. Furthermore, the TaM clock outperformed the TaC clock at capturing a significant increase in epigenetic age in Down syndrome, Werner syndrome and HIV. We subsequently developed digital PCR assays to analyse 446 samples from the ActiFE cohort. One TaM clock site (cg20595453) showed significant association with both mortality and frailty. However, predictions generated by either targeted clock were not significantly associated with mortality and there was no clear relationship with frailty or age-related clinical parameters in this larger cohort.</p><p><strong>Conclusion: </strong>Our targeted signatures were not sensitive enough to reliably predict frailty or mortality in a relatively healthy study population, which seems to be a general challenge for epigenetic clocks. It may be necessary to include additional disease-associated target sites to support frailty analysis in personalized medicine.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13339440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epstein-Barr Virus-host epigenetic interplay: mechanisms of regulation and therapeutic potential.","authors":"Sanaz Baghban Rahimi, Ahmad Hosseinzadeh Adli, Hossein Bannazadeh Baghi, Vahdat Poortahmasebi, Jamal Sarvari","doi":"10.1186/s13148-026-02181-2","DOIUrl":"10.1186/s13148-026-02181-2","url":null,"abstract":"<p><p>The Epstein-Barr virus (EBV) has evolved complex mechanisms to manipulate the host immune system and epigenetic machinery, enabling it to establish lifelong latent infection within host cells. Emerging evidence strongly indicates that the EBV acts as a main epigenetic manipulator by silencing host regulatory genes, altering host chromatin landscapes and exploiting B-cell biology. Key mechanisms include viral-mediated recruitment of host DNA methyltransferases and histone-modifying enzymes; modulation of host non-coding RNAs and chromatin architectural factors; and targeted disruption of interferon signaling through RNA methylation and restructuring of host chromatin. These integrated processes allow EBV to maintain a lifelong infection in humans, evade both innate and adaptive immunity, and respond to reactivation signals. Understanding the virus-host epigenetic interplay offers new opportunities for therapeutic interventions targeting epigenetic regulators in EBV-associated diseases.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic signatures of cardiometabolic risk in men: accelerated aging and differential methylation replicated across cohorts.","authors":"Alena Kalyakulina, Igor Yusipov, Faina Botasheva, Nadezhda Bujlova, Elena Zagaynova, Claudio Franceschi, Mikhail Ivanchenko","doi":"10.1186/s13148-026-02195-w","DOIUrl":"10.1186/s13148-026-02195-w","url":null,"abstract":"<p><strong>Background: </strong>Men exhibit greater susceptibility to cardiovascular diseases and metabolic disorders, with an earlier onset and more aggressive progression, potentially driven by epigenetic modifications, particularly DNA methylation. Our goal was to comprehensively characterize the epigenetic landscape of a broad cardiometabolic burden in a cohort composed exclusively of men.</p><p><strong>Results: </strong>We generated novel DNA methylation profiles from whole blood samples of men with cardiometabolic disturbances (hypertension, ischemic heart disease, obesity, dyslipidemia) and age-matched healthy controls. Cases demonstrated significant epigenetic age acceleration, most pronounced for second-generation clocks (GrimAge, GrimAge2) and pace of aging measures (DunedinPACE), accompanied by shortened epigenetic telomere length (DNAmTL). Notably, none of the 19 evaluated first-generation epigenetic clocks exhibited sensitivity to the studied diseases. Epigenome-wide association analysis identified differentially methylated positions (DMPs), predominantly hypomethylated in cases compared to controls. Gene set enrichment analysis of genes annotated to these DMPs revealed nine distinct biological pathway clusters that reflect the multifactorial processes associated with cardiometabolic burden, including chronic inflammation, GPCR signaling dysregulation, metabolic disturbances, mitochondrial dysfunction, vascular remodeling, and renal electrolyte regulation. Key findings, including GrimAge acceleration, DunedinPACE elevation, DNAmTL shortening, and enrichment of inflammatory and GPCR pathways, were replicated in an independent cohort of men with atherosclerosis.</p><p><strong>Conclusions: </strong>Men with cardiometabolic disturbances exhibit accelerated epigenetic aging and distinct DNA methylation signatures associated with cardiometabolic burden. Analysis of a broad battery of epigenetic clock models revealed that only the second-generation (GrimAge) and third-generation (DunedinPACE) models demonstrated a pronounced sensitivity to the uncomplicated diseases evaluated. In contrast, the first-generation models, trained to predict chronological age, failed to detect significant differences between the groups, suggesting limited applicability in these pathologies. The concordance of results across original and independent replication cohorts underscores the fundamental nature of these epigenetic alterations. Our findings suggest candidate biomarkers measurable in minimally invasive blood samples that may assist in early risk stratification and monitoring of disease progression in men, warranting further prospective evaluation to facilitate clinical translation.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TCA-controlled histone succinylation identifies IDH3B as a prognostic and therapeutic target in AML.","authors":"Minhui Shi, Kepeng Yang, Hao Ding, Na Zhao, Jiewen Ma, Aijie Huang, Yun Wang, Xiaoyu Zhu, Domenico Iuso, Mengqing Gao","doi":"10.1186/s13148-026-02197-8","DOIUrl":"10.1186/s13148-026-02197-8","url":null,"abstract":"<p><strong>Background: </strong>Mitochondrial metabolism-driven epigenetic modifications have emerged as crucial regulators for acute myeloid leukemia (AML) progression, linking metabolic activity in leukemic stem cells to epigenetically controlled transcriptional programs that drive oncogenic gene expression.</p><p><strong>Results: </strong>Here, by integrating proteomic and transcriptomic data, we identified six genes whose expression were able to predict outcome in AML. Among these, IDH3B was highly expressed in leukemic stem cells and associated with poor prognosis. Functional studies revealed that IDH3B deletion in KMT2A-rearranged AML increased global protein succinylation, reduced acetylation, and sensitized cells to the menin-KMT2A inhibitor, both in vitro and in vivo. Mechanistically, loss of IDH3B, by increasing histone succinylation and reducing H3K79 methylation at the MYC promoter, amplified Revumenib-induced transcriptional repression of MYC.</p><p><strong>Conclusions: </strong>These findings establish IDH3B as a key metabolic-epigenetic regulator in AML and highlight it as a potential synergistic target to enhance menin inhibition therapy.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148389442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of epigenetic age acceleration and social disadvantage in cardiometabolic health in southeast Louisiana women.","authors":"Alicia K Smith, Seyma Katrinli, Julian L Moran, Kristyne D Mansilla Dubon, Sierra N Garth, Michael Simmond, Dawayland O Cobb, Meghan Brashear, Edward J Trapido, Erika J Wolf, Ariane L Rung, Nicole R Nugent, Edward S Peters","doi":"10.1186/s13148-026-02183-0","DOIUrl":"10.1186/s13148-026-02183-0","url":null,"abstract":"<p><strong>Background: </strong>Cardiometabolic risk factors can disrupt DNA methylation (DNAm) patterns, accelerate cellular aging, and contribute to age-related disorders, including cardiovascular disease (CVD) and diabetes. Social disadvantage may exacerbate these biological processes, yet its relationship with epigenetic aging and cardiometabolic disease across time remains incompletely understood. We examined associations between epigenetic age acceleration and both social disadvantage and cardiometabolic diseases. We assessed whether these associations differed in each study wave.</p><p><strong>Results: </strong>Participants were drawn from The Women and Their Children's Health (WaTCH) cohort and assessed at Wave 1 (2012-2014; N = 865) and Wave 3 (2023-2025; N = 348). At Wave 1, participants had a mean age of 46.9 ± 11.9 years and identified as Black (38.0%) or White (56.2%). Social disadvantage was assessed using an individual-level socioeconomic status (SES) index (education, income, and health insurance) and the Area Deprivation Index (ADI). DNAm was measured from blood samples to derive epigenetic age acceleration metrics (GrimAge2, PhenoAge, and DunedinPACE). Lower SES index and higher ADI were associated with greater epigenetic age acceleration and a faster pace of aging. CVD (45.2%) and diabetes (15.6%) at Wave 1 were more prevalent among participants with lower SES index, higher ADI, Black race, and higher body mass index (BMI). After adjustment for BMI, alcohol use, ADI, SES, smoking, and cell composition, both CVD and diabetes were associated with higher GrimAge2 and PhenoAge acceleration and a faster pace of aging at Wave 1. At Wave 3, diabetes was associated with all measures of epigenetic age acceleration after covariate adjustment.</p><p><strong>Conclusions: </strong>CVD and diabetes were more common among socially disadvantaged women and were associated with accelerated epigenetic aging. These findings highlight the biological correlates of social disadvantage and underscore the need for targeted public health interventions addressing social drivers of health to mitigate cardiometabolic disease risk.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Azacitidine and decitabine show distinct response patterns in pediatric Myelodysplastic Syndromes and Juvenile Myelomonocytic Leukemia before HSCT: a systematic review and quantitative analysis.","authors":"Alessandra Cianflone, Francesco Cecere, Luigi Coppola, Fabiana Cacace, Peppino Mirabelli, Francesco Paolo Tambaro","doi":"10.1186/s13148-026-02191-0","DOIUrl":"10.1186/s13148-026-02191-0","url":null,"abstract":"<p><strong>Background: </strong>Epigenetic dysregulation is a key therapeutic target in pediatric hematologic malignancies resistant to conventional chemotherapy, where allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option. In this setting, hypomethylating agents (HMAs), such as azacitidine (AZA) and decitabine (DAC), are increasingly used as pre-transplant bridging strategies to reduce disease burden and enhance treatment sensitivity. Their integration with HSCT may improve pre-transplant remission rates, prolong complete remission, and increase the likelihood of durable disease control and cure. However, evidence in pediatric patients remains limited. Here, we performed a systematic review and pooled analysis to evaluate the efficacy of pre-HSCT epigenetic therapy in pediatric hematologic malignancies.</p><p><strong>Results: </strong>A pooled analysis of seven studies of 87 pediatric patients including 51 Myelodysplastic Syndromes (MDS) and 36 Juvenile Myelomonocytic Leukemia (JMML) treated with DAC or AZA prior to HSCT was performed. Statistical analyses used chi-squared or Fisher's exact tests for categorical variables and non-parametric tests for continuous variables, with correction for multiple comparisons. In MDS, Complete remission (CR) was achieved in 64.7% of patients and strongly associated with DAC, translating into improved post-HSCT survival compared to PD (84.2% vs. 42.8%). In JMML, partial remission (PR) and progressive disease (PD) predominated (47.2% and 41.7%, respectively), while CR was rare (11.1%); response was not associated with HMA type or genetic features, although older age correlated with PD. Comparative analysis confirmed superior responses in MDS (higher CR and SD) versus JMML, which showed higher PR and PD rates. PTPN11 mutations were significantly associated with multiple clinical variables, including treatment response.</p><p><strong>Conclusions: </strong>Pre-transplant HMA therapy shows variable efficacy in pediatric myeloid malignancies. DAC induces rapid, deep responses in MDS, improving post-HSCT survival. JMML responds less, yet post-transplant survival remains favorable. Higher HMA responsiveness in MDS likely reflects predominant epigenetic dysregulation, whereas JMML is mainly driven by aberrant RAS/MAPK pathway activation. These results emphasize that pre-transplant strategies should be tailored to the specific biological and clinical context of each disease. However, their impact relative to upfront HSCT or conventional chemotherapy remains to be definitively determined.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetics-mediated pathological alterations and their diagnostic and therapeutic potential in sepsis-associated acute kidney injury.","authors":"Qian Zhang, Yuan Tan, Jingjin Tao, Boxin Yang, Zhen Xu, Shuo Yang, Liyan Cui","doi":"10.1186/s13148-026-02190-1","DOIUrl":"10.1186/s13148-026-02190-1","url":null,"abstract":"<p><p>Sepsis-associated acute kidney injury (SA-AKI) is a prevalent and life-threatening condition among critically ill patients. At present, studies on SA-AKI are still in the experimental stage, and comprehensively elucidating the pathogenesis of SA-AKI would effectively promote the development of diagnostic and therapeutic for SA-AKI. Emerging evidence highlights the critical role of cell-specific epigenetic dysregulation in the severity and progression of SA-AKI, particularly in monocytes, macrophages, neutrophils, endothelial cells (ECs), and renal tubular epithelial cells (RTECs). Classical epigenetic modifications, including DNA methylation and histone modifications, serve as pivotal regulators of gene transcription, influencing multiple pathological processes, including inflammatory responses, microcirculatory dysfunction, and metabolic reprogramming during SA-AKI. Therefore, this review aims to provide a comprehensive analysis of the underlying epigenetic mechanisms of SA-AKI progression and explore the potential of epigenetic markers as diagnostic tools and therapeutic targets. Finally, we propose that targeting epigenetic modifications could pave the way for novel diagnostic strategies and precision medicine to improve SA-AKI outcomes.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13584438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148351118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of tobacco smoking on estimated telomere shortening and epigenetic age acceleration among human blood immune cell types.","authors":"Xuting Wang, Michelle R Campbell, Suzanne N Martos, Jian-Liang Li, Douglas A Bell","doi":"10.1186/s13148-026-02187-w","DOIUrl":"10.1186/s13148-026-02187-w","url":null,"abstract":"<p><strong>Background: </strong>Tobacco smoke exposure has been shown to dramatically alter the methylome of whole blood DNA, and we have previously observed that effects are very different among blood cell types. In the present work, we compare smoking effects on DNA methylation-based telomere length (DNAmTL) shortening, age acceleration (DNAmAA) of 6 DNAmAge clocks (Horvath, Hannum, Skin_Blood, PhenoAge, FitAge, GrimAge2), aging pace (DunedinPACE), and Stochastic Epigenetic Mitotic Timer of Cancer (stemTOC) in six major immune cell types isolated from the whole blood samples of the same individuals from 74 nonsmokers and 69 smokers.</p><p><strong>Results: </strong>Telomere shortening in all cell types was significantly associated with smoking status, with smokers displaying greater telomere shortening. Examining the difference in DNAmTL shortening between smokers and nonsmokers across cell types, CD8+ T cells had the greatest DNAmTL shortening, while CD15+ granulocytes had the least shortening. Among six DNAmAge models tested, the strongest association between DNAmAge Acceleration (DNAmAA) and smoking status was observed for the GrimAge2 model, followed by the FitAge model and then the PhenoAge model, with smokers displaying greater age acceleration. For the GrimAge2 and FitAge models, as expected, smokers revealed greater age acceleration in whole blood samples. Across all cell types, the effect size in epigenetic age acceleration associated with smoking was significantly correlated with smoking effect as measured by mean AHRR cg05575921 demethylation values, with myeloid cell types showing the greatest effect and T cells least. However, the Hannum, Horvath, and Skin_Blood models (which were trained only by chronological age) were generally not significantly associated with smoking status in isolated cell types. We observed the DunedinPACE model was significantly associated with smoking status in all cell types and whole blood samples. Smokers had significantly higher aging pace in all cell types relative to nonsmokers. The stemTOC was not significantly associated with smoking status in isolated cell types.</p><p><strong>Conclusions: </strong>The present study demonstrates that tobacco smoking is significantly associated with methylation-based measures of telomere length shortening, biological age acceleration, and aging pace in six major immune cell types and whole blood. The effect of smoking on these outcomes differs among cell types, suggesting shifts in cell composition may play an important role in human aging as measured by DNA methylation models and epigenetic aging may play a role in smoking-related diseases.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic collapse establishes transcriptional bottlenecks in malignant rhabdoid tumor.","authors":"Tatsuya Masuda, Takayoshi Watanabe, Toshinori Ozaki, Yasuhiko Kamikubo","doi":"10.1186/s13148-026-02170-5","DOIUrl":"10.1186/s13148-026-02170-5","url":null,"abstract":"<p><p>Malignant rhabdoid tumor (MRT) is an aggressive pediatric cancer defined by biallelic loss of SMARCB1 and characterized by an unusually simple mutational landscape. Despite the absence of recurrent activating oncogenic mutations, MRT exhibits highly malignant behavior, creating a clinical paradox. Loss of SMARCB1 disrupts SWI/SNF-mediated chromatin organization, leading to enhancer redistribution and reorganization of transcriptional control. MRT therefore provides a defined model to examine how structural disruption of chromatin regulation sustains tumor maintenance in the absence of mutation-driven signaling activation. We propose that this epigenetic collapse reduces regulatory diversity and concentrates control of essential survival and cell-cycle programs within limited transcriptional nodes. We define this structural state as transcriptional bottleneck formation, in which tumor viability depends on concentrated transcriptional control rather than recurrent genetic alteration. Bottleneck nodes are characterized by enriched chromatin occupancy at survival and cell-cycle genes, limited compensatory regulation, and functional sensitivity to perturbation. In MRT, members of the RUNX family illustrate a representative concentrated transcriptional node linking chromatin reorganization to regulation of BIRC5 and related survival genes. This disease-focused perspective supports an architecture-centered therapeutic strategy aimed at disrupting concentrated transcriptional control. Identification of biomarkers reflecting this architectural state may facilitate selection of bottleneck-directed interventions in MRT.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148316246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and epigenetic underpinnings of biological aging: a multi-omics study integrating Mendelian randomization, spatial transcriptomics, and drug target discovery.","authors":"Chun Zhang, Jingqi Zhang","doi":"10.1186/s13148-026-02184-z","DOIUrl":"10.1186/s13148-026-02184-z","url":null,"abstract":"<p><p>Inflammaging represents a hallmark of biological aging, yet the causal inflammatory mediators driving multi-dimensional epigenetic aging and their effector genes remain poorly characterized at the genetic level. We developed a four-tier analytical framework integrating causal screening, multi-omics effector gene mapping, spatial transcriptomics, and drug target evaluation. Two-sample Mendelian randomization (MR) of 91 circulating inflammatory proteins against six aging phenotypes identified IL-12B, IFNG, and IL-2 as the most robust pro-aging mediators with consistent effects across independent outcomes. Using multi-omics summary-based MR (SMR) as the core analytical engine, we integrated four-layer whole-blood molecular QTL resources eQTL (eQTLGen, n = 31,684), sQTL (GTEx, n = 755), pQTL (INTERVAL + SCALLOP, n = 34,232), and mQTL (McRae et al., n = 1,980) - with GWAS summary statistics for four epigenetic age acceleration measures. At a stringent threshold (P_SMR < 1×10⁻¹²), seven high-confidence effector genes were identified: NHLRC1, TPMT, SELP, and RIPPLY3 for IEAA; ZNF373A and PLDN for HannumAA; and EDARADD for PhenoAA. The chromosome 6p21 NHLRC1-TPMT locus, overwhelmingly driven by methylation QTL signals (-log₁₀P = 26.06), emerged as the dominant genetic node of epigenetic aging. Spatial projection via gsMap onto a mouse E16.5 embryo atlas (121,767 cells) revealed preferential enrichment in smooth muscle and lung, with EDARADD showing marked specificity in mucosal epithelium. Cross-database drug target mining classified TPMT and SELP as repurposable known targets and NHLRC1 as a high-priority novel druggable candidate. This study provides multi-omics convergent causal evidence for inflammation-driven epigenetic aging and delivers genetically anchored targets for precision anti-aging intervention.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148316205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}