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Results for “GrimAge”

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PubMed2025

Developmental timing of index trauma exposure and accelerated epigenetic aging in United States military veterans.

Trauma exposure has been linked to accelerated GrimAge, an epigenetic biomarker of premature morbidity and mortality. Building on this evidence, the present study examined whether the type and timing of index trauma exposure are differentially associated with accelerated GrimAge. Participants were 873 European American male United States military Veterans from the National Health and Resilience in Veterans Study. We investigated associations between self-reported age at index trauma, index trauma type (interpersonal violence, non-interpersonal trauma, or loss/instability/other), and accelerated GrimAge, operationalized as GrimAge exceeding chronological age by five or more years. Results revealed that interpersonal violence was associated with three-fold greater odds of accelerated GrimAge compared to other trauma types. Age at index trauma was not independently associated with accelerated GrimAge. However, we observed a significant interaction between trauma type and its developmental timing, even after adjusting for index trauma recency, cumulative trauma burden, and other potential confounders. Specifically, Veterans who were older at the time of exposure to interpersonal violence or trauma involving loss or instability had higher odds of accelerated GrimAge. In contrast, exposure to non-interpersonal trauma was more strongly associated with accelerated GrimAge when it occurred at younger ages. These results indicate that trauma type and timing jointly influence epigenetic aging in Veterans, highlighting the need for tailored interventions that address specific trauma characteristics to reduce associated long-term health risks in this population.

Humans↗

PubMed2026

Accelerated Biological Aging Increases the Risk of Head and Neck Cancer: Insights From Genetic Instruments of Epigenetic Clocks.

Epigenetic clocks are robust biomarkers of biological aging and have been associated with cancer susceptibility. However, the relationship between genetically predicted epigenetic age acceleration and head and neck cancer risk remains unclear. Using a large case-control study of 2189 head and neck squamous cell carcinoma (HNSCC) cases and 2189 age- and sex-matched controls, we investigated the associations between polygenic scores (PGSs) for multiple epigenetic clocks and HNSCC risk, and evaluated their potential causal roles using two-sample Mendelian randomization (MR). Genome-wide association study (GWAS)-identified single nucleotide polymorphisms (SNPs) associated with four epigenetic clocks (HannumAge, HorvathAge, GrimAge, and PhenoAge) were used to construct clock-specific PGSs. Logistic regression models were applied to assess associations between PGSs and HNSCC risk, while MR analyses, including inverse-variance weighted (IVW), weighted median, and MR-Egger methods, were used to infer potential causal relationships. Among the 48 epigenetic clock-associated SNPs, 12 showed nominal associations with HNSCC risk, and one variant (rs2275558 in PBX1) remained significant after Bonferroni correction (OR = 0.67, 95% CI: 0.60-0.76). PGSs for all four epigenetic clocks were higher in cases than in controls. In logistic regression analyses, each standard deviation increase in HannumAge PGS was associated with a 25% higher risk of HNSCC (OR = 1.25, 95% CI: 1.10-1.41), whereas HorvathAge, GrimAge, and PhenoAge PGSs showed weaker positive associations (ORs ranging from 1.06 to 1.10). Individuals in the highest PGS quartile for all four epigenetic clocks exhibiting 14%-25% higher risk than those in the lower three quartiles. MR analyses supported potential causal effects of genetically predicted HannumAge (IVW OR = 1.24 per SD increase, 95% CI: 1.09-1.42) and GrimAge (IVW OR = 1.23 per SD increase, 95% CI: 0.98-1.56) on HNSCC risk, with consistent estimates in weighted median analyses. Our results highlight biological aging as a potential etiologic mechanism for HNSCC and suggest that epigenetic clock-related genetic profiles may improve HNSCC risk stratification.

Humans↗

PubMed2026

Epigenetic aging of colorectal mucosa in cancer development.

BACKGROUND: The past decade has seen the development of epigenetic models of aging that accurately estimate chronological age and predict disease incidence and mortality. These estimates are modulated by lifestyle and environmental factors linked to carcinogenesis, but to date this has primarily been studied in blood. METHODS: We examined epigenetic aging in normal colonic tissue (n = 96), adjacent mucosa (n = 245) and tumors (n = 208), using models trained on age (Horvath, Hannum, Zhang), mortality (PhenoAge, GrimAge), aging rate (DunedinPACE), cellular mitotic history (EpiTOC, epiTOC2, miAGe), and telomere length (DNAmTL). RESULTS: The Horvath model was the most accurate estimator of chronological age in normal colonic mucosa, with high correlation (r > 0.70) between the Horvath, Hannum, Zhang, PhenoAge and GrimAge models, and between mitotic clocks (r > 0.94). All models showed similar performance in normal tissue and adjacent mucosa, but substantially more variation in estimates in tumors. Significant differences in age acceleration were present between normal and adjacent mucosa by six models (Hannum, Zhang, PhenoAge, EpiTOC, epiTOC2 and miAge), while tumors showed highly significant differences by all models. Age acceleration differed by region of the colon, with varying patterns by model type. Physical activity (PhenoAge), smoking history (GrimAge), and alcohol consumption (Horvath, mitotic clocks) were associated with epigenetic aging in adjacent mucosa, while smoking history, smoking intensity, and alcohol consumption were associated with DNAmTL in tumors. CONCLUSIONS: Our study reveals an impact of tissue type, region, and lifestyle factors on epigenetic aging, but also highlights significant heterogeneity between models and the need for careful consideration within study design.

DNA methylation↗

PubMed2026

Clonal haematopoiesis of indeterminate potential and epigenetic age acceleration: Systematic review and meta-analysis.

Clonal haematopoiesis of indeterminate potential (CHIP) represents somatic mutations in haematopoietic stem cells that drive clonal expansion. Epigenetic age acceleration (EAA), estimated from DNA methylation (DNAm) clocks, may capture age-related changes in haematopoiesis. This systematic review and meta-analysis was conducted to synthesise evidence on associations between CHIP and EAA and explore shared biological mechanisms that may underlie this relationship. Six databases were searched from January 1, 2011, to June 6, 2025, adhering to PRISMA 2020. Random-effects meta-analyses were performed. Five studies comprising 7483 individuals (ages 55-79, 67.1% female) assessing associations between CHIP and DNAm clocks were included. Across studies, CHIP individuals had higher EAA than no-CHIP individuals, and larger clones were associated with higher EAA. Meta-analysis of three cross-sectional studies (n = 6946) showed that CHIP had higher EAA versus no-CHIP for Horvath1Age IEAA (mean difference, MD=2.84 years, 95% confidence interval, CI: 1.49-4.19), HannumAge EEAA (MD=2.31 years, 95% CI: 1.14-3.49), PhenoAge (MD=1.84 years, 95% CI: 0.96-2.71), and GrimAge (MD=1.20 years, 95% CI: 0.80-1.61). Both DNMT3A- and TET2-mutated CHIP were associated with higher EAA with TET2-mutated CHIP showing larger effect sizes and more consistent associations than DNMT3A-mutated CHIP across DNAm clocks tested. Higher EAA may also act as an effect modifier for morbidity and mortality in CHIP. Larger longitudinal studies are needed to verify a temporal relationship and determine whether EAA provides incremental prognostic value for morbidity and mortality in CHIP.

Humans↗

PubMed2026

Epigenetic aging and autosomal methylation remodeling in Anderson-Fabry disease.

Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disorder characterized by marked clinical heterogeneity and incompletely understood genotype-phenotype correlations. While X-chromosome inactivation has been extensively investigated, the contribution of autosomal epigenetic mechanisms to phenotypic variability remains poorly defined. Here, we performed an exploratory genome-wide DNA methylation analysis in 32 AFD patients (22 females and 10 males; mean age 51.7 years) recruited within a multicenter regional research project in Calabria (Italy). DNA methylation profiling was conducted using the Infinium MethylationEPIC v2.0 array. The analysis integrated two complementary approaches: differential methylation analysis and evaluation of biological aging through multiple epigenetic clocks, including Horvath, Hannum, PhenoAge, Skin & Blood, GrimAge, and DunedinPACE. Exploratory methylome-wide analysis identified a limited set of CpG loci showing nominal evidence of methylation differences between carriers of pathogenic and non-pathogenic variants; however, none remained statistically significant after correction for multiple testing. Annotation of the top-ranking nominal CpG associations highlighted genes involved in biological processes including vascular regulation, intracellular trafficking, cytoskeletal organization, immune signaling, and lipid metabolism. No significant differences between groups were observed for the conventional epigenetic age-acceleration measures examined. In contrast, carriers of pathogenic variants showed significantly higher DunedinPACE values (p = 0.0328), indicating a faster estimated pace of biological aging. This finding suggests that DunedinPACE may capture aspects of the cumulative systemic burden associated with pathogenic GLA variants, although confirmation in larger independent cohorts is required. Overall, this pilot epigenomic study provides preliminary evidence that autosomal epigenetic remodeling and biological aging acceleration may contribute to phenotypic heterogeneity in AFD.

Anderson-Fabry disease↗

PubMed2026

Ensemble DNA methylation clock demonstrates Immune-metabolic aging signatures associated with mortality.

Aging is a multifactorial process that is best described in terms of the progressive acquisition of multiple layers of phenotypic changes, such as epigenetic modifications, inflammation, and metabolic dysregulation. DNA methylation clocks have been extensively used to construct epigenetic clocks based on the DNAm profiles that can be used to estimate biological age and predict age-associated outcomes. Nevertheless, the vast majority of clocks constructed so far have been based on linear models, which are unlikely to fully account for the heterogeneity and non-linearity of survival-related DNAm signatures. In this work, we constructed a heterogeneous stacked ensemble survival model based on DNAm data obtained from the Framingham Heart Study. We first identified 190 CpG loci using elastic net Cox regression and subsequently constructed a survival prediction model based on the fusion of five complementary survival models by means of a neural network meta-learner. The prediction power of the survival model was evaluated in an external validation cohort, where we observed strong performance for predicting all-cause mortality that significantly exceeded PhenoAge and was statistically comparable to GrimAge. These performance estimates were derived in cohorts of European ancestry and externally validated in postmenopausal women aged 50-79 years, and should therefore be interpreted as applicable only to demographically similar populations.

Humans↗

PubMed2025

Genome-wide methylation biomarkers and biological aging in patients with bipolar disorder characterized for lithium response.

BACKGROUND: Epigenetic mechanisms might play a role in modulating susceptibility to bipolar disorder (BD) and response to lithium, the mainstay treatment for BD. Additionally, individuals with BD experience accelerated biological aging. METHODS: We compared blood DNA methylation profiles measured with EPIC v.2.0 arrays between patients with BD (33 lithium responders and 31 nonresponders) and nonpsychiatric controls (n = 32), as well as based on long-term lithium response. In addition, we compared cellular aging between these groups using epigenetic age, pace of aging, and, for the first time, transcriptional age acceleration based on bulk RNA sequencing in 93 patients and 56 controls. RESULTS: We identified 191 differentially methylated positions (DMPs) and 8 differentially methylated regions between patients with BD and controls, located in genes enriched for "Postsynaptic Density" (odds ratio = 6.81, p = 0.001). No DMP was significantly associated with lithium response after multiple testing correction. Patients showed a significantly higher biological age acceleration than controls based on two epigenetic clocks (GrimAge, Mann-Whitney U = 551, p = 0.0009; GrimAge2: U = 477, p = 9.0E-05) and pace of aging (DunedinPACE, t = 3.01, p = 0.003), but not on transcriptional age. While we observed no significant difference in epigenetic aging based on lithium response, lithium responders showed lower epigenetic acceleration using all clocks, with a trend observed using the PhenoAge clock (t = 1.97, p = 0.053). CONCLUSIONS: Our findings point to methylation patterns characterizing BD and support the hypothesis of accelerated cellular aging in BD.

Humans↗

PubMed2026

The effects of tildrakizumab in the epigenetic aging deviation of psoriasis: A 52-week open-label study.

BACKGROUND: While biologic therapies targeting interleukin-23 control cutaneous inflammation in psoriasis, their impact on epigenetic aging has not been previously demonstrated. OBJECTIVES: To evaluate the effects of tildrakizumab treatment in the epigenetic aging deviation of moderate-to severe psoriasis. METHODS: In an open-label 52-week clinical trial, 20 adults with psoriasis were treated with tildrakizumab-asmn 100 mg injections until week 28. Ten age-matched controls without psoriasis were enrolled. Genome-wide DNA methylation was profiled in peripheral blood leukocyte DNA (MethylationEPICv2.0, Illumina) to calculate epigenetic aging clocks predictive of all-cause-mortality, phenotypic age, chronological age, pace of aging, and telomere length. Epigenetic age deviation was calculated as the residuals against chronological age. RESULTS: Psoriasis patients had increased epigenetic age deviation in clocks predictive of mortality: PCGrimAge (P = .008), cytosine-phosphate-guanine (CpG) PTPCGrimAge3 (P = .019), CpGPTGrimAge3 (P = .019), GrimAge2 (P = .049). PCGrimAge was reversed by 0.3 years (week 28, P = .005) and 0.5 years (week 52, P = .04) after the use of tildrakizumab-asmn. The pace of aging was increased in psoriasis patients: DunedinPACE (P = .049). LIMITATIONS: Pilot study (small sample size). CONCLUSIONS: Psoriasis patients presented accelerated epigenetic aging in mortality-predictive clocks. Treatment with tildrakizumab-asmn (interleukin-23 inhibition) showed partial reversal of those clocks in 28 weeks. (Funded by Sun Pharmaceutical Industries, Inc; ClinicalTrials.gov number, NCT05110313).

DNA methylation clocks↗