Aug 2026· Biomedicines· Vol 14, pp. 1792· 0 citations· 47 references
Medicine
TL;DR
Although associations with fibrosis-related outcomes varied according to fibrosis definitions, DNAm aging algorithms may provide additional biological information for mortality risk stratification among individuals with CLD-related phenotypes.
Abstract
Background: Chronic liver disease (CLD) represents a substantial global health challenge, with significant morbidity and mortality worldwide. Biological aging may be involved in CLD-related outcomes, but the associations of diverse DNA methylation (DNAm) aging algorithms with CLD phenotypes and long-term mortality remain incompletely characterized. Methods: Using a US nationally representative cohort, we analyzed 12 DNAm aging algorithms in 2522 adults aged ≥50. CLD was classified into viral, alcohol-related, metabolic syndrome (MetS)-related liver disease, or uncharacterized groups. Advanced fibrosis was defined by AST-to-platelet ratio index ≥0.7. Associations of algorithms with CLD and all-cause mortality (followed through 2019) were assessed using multivariable-adjusted regression and logistic regression models and Cox models, accounting for complex sampling. Results: Among participants with CLD, DNAm aging algorithms showed only nominal associations with APRI-defined advanced fibrosis. GrimAgeMortAcc, GrimAge2MortAcc, HannumAgeAcc, PhenoAgeAcc, DunedinPoAm, and HorvathTelo were significantly associated with all-cause mortality. GrimAge-based measures and PhenoAgeAcc showed the strongest associations with all-cause mortality across CLD-related phenotypes (HRs ranged from 1.31 to 1.82). HorvathTelo was inversely associated with mortality risk (HR = 0.71, 95% CI: 0.62–0.82). Conclusions: DNAm aging algorithms, particularly GrimAge-based measures, are strongly associated with long-term all-cause mortality among individuals with CLD-related phenotypes. Although associations with fibrosis-related outcomes varied according to fibrosis definitions, DNAm aging algorithms may provide additional biological information for mortality risk stratification among individuals with CLD-related phenotypes.
End-stage renal disease (ESRD) remains a major clinical challenge with high morbidity and mortality, and its molecular mechanisms, particularly those shared among diverse primary kidney diseases during progression to ESRD, have not been studied. Here we conduct a large-scale two-stage epigenome-wide association study of ESRD in two independent cohorts consisting of 704 controls and 1031 ESRD cases. We identify 52 ESRD-associated differentially methylated CpG positions (ESRD DMPs) showing consistent association between the two cohorts and across diverse kidney diseases, implicating 144 candidate genes enriched in inflammatory and immune pathways. Five of the 52 DMPs are associated with ESRD complications, and seven with renal function decline in early-stage chronic kidney disease, demonstrating their potential as prognostic biomarkers for ESRD and its complications. Our findings highlight inflammation, immune dysregulation, and renal fibrosis as shared epigenetic drivers of ESRD progression, and identify biomarkers with potential utility for risk stratification and therapeutic intervention. A two-stage epigenome-wide study identified 52 DNA methylation markers associated with end-stage renal disease across diverse primary kidney diseases, highlighting the shared roles of inflammation, immune dysregulation, and renal fibrosis.
BACKGROUND
While conventional risk factors for liver cancer are well-established, the contribution of biological aging to hepatocarcinogenesis remains poorly understood, representing an important gap in its etiological framework.
METHODS
We conducted a prospective cohort study using data from the UK Biobank (UKB). Biological age (BA) was assessed using the Klemera-Doubal method (KDM-BA) and PhenoAge algorithms. Multivariable Cox proportional hazards models were used to evaluate associations between BA acceleration and liver cancer incidence, with robustness assessed using restricted cubic splines, subgroup analyses, and sensitivity analyses. Mediation analyses evaluated whether alanine aminotransferase (ALT) and aspartate aminotransferase (AST) mediate the relationship between biological aging and liver cancer.
RESULTS
The study included 274,966 participants (mean age 55.75 ± 8.10 years; 53.8% female). Over a median follow-up of 14.67 years, 325 incident liver cancer cases were documented. After multivariable adjustment, each 1-standard deviation (SD) increase in BA acceleration was associated with an elevated liver cancer risk (KDM-BA acceleration: HR = 1.28, 95%CI 1.16-1.41; PhenoAge acceleration: HR = 1.32, 95%CI 1.22-1.43). A nonlinear dose-response relationship was observed between KDM-BA acceleration and liver cancer risk (P < 0.001). Exploratory mediation analyses indicated that the effect of KDM-BA acceleration may be partially mediated by ALT and AST, whereas PhenoAge acceleration appeared to act primarily through direct mechanisms.
CONCLUSIONS
Accelerated biological aging, as quantified by KDM-BA and PhenoAge, appears to be independently associated with incident liver cancer. The underlying pathways may differ: KDM-BA acceleration is partially mediated by liver enzymes, while PhenoAge acceleration appears to operate largely through direct mechanisms.
DunedinPoAm predicts all-cause mortality in a non-linearly manner across multiethnic populations, partially mediated by pathways associated with inflammaging, and the observed diabetes-specific interactions and threshold effects indicate the potential for precision approaches targeting high-risk subgroups.
Jihua Feng, Yu-Ting Liang, Jie Zhou et al.· Clinical Epigenetics· 0 citations
BACKGROUND
Biological aging is a well-established risk factor for age-related diseases. However, its specific impact on patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study aimed to investigate the association between biological aging and premature mortality among patients with MASLD.
METHODS
Data from 10,933 participants in the National Health and Nutrition Examination Survey (NHANES) were analyzed. Biological aging was quantified using the Gompertz Law-Based Biological Age (GOLD BioAge) metric. Accelerated biological aging was determined by calculating the difference between biological age and chronological age. Logistic regression models were applied to assess the cross-sectional association between biological aging and MASLD. Within the MASLD cohort, Fine‑Gray competing risks model were used to evaluate the longitudinal relationship between biological aging and premature mortality. Additionally, restricted cubic spline (RCS) analysis was performed to assess potential nonlinear associations.
RESULTS
Among all participants, a significant linear association emerged between GOLD BioAgeDiff and MASLD(OR = 1.11, 95% CI: 1.09-1.13, p < 0.001). Participants with biological age acceleration had significantly higher odds of MASLD compared with those without acceleration (OR = 2.13, 95% CI: 1.82-2.50, p < 0.001). Among the 3849 participants with MASLD, GOLD BioAgeDiff showed a linear association with premature mortality. Compared with the first tertile (T1), the cumulative incidence of premature mortality was significantly higher in T3 (SHR = 4.05, 95% CI:2.32-7.07, p < 0.001). Participants with biological age acceleration had a 139% higher cumulative incidence of premature mortality compared to those without acceleration (HR = 2.39, 95% CI: 1.56-3.66, p < 0.001).
CONCLUSION
This study demonstrated a significant association of GOLD BioAgeDiff with MASLD. Biological age acceleration increases the cumulative incidence of premature mortality among individuals with MASLD.
Song-Lin Li, Bao-Gang Chen· Archives of gerontology and...· 0 citations
Higher urinary DETP was associated with greater heart disease mortality in middle-aged and older adults, and in vitro experiments provided hypothesis-generating support—most directly for inflammatory signaling—rather than confirmation of the epidemiological pathway.
Yun-Li Song, Li-Hui Liang, Jing Hao et al.· Frontiers in Public Health· 0 citations
Background: DNA methylation (DNAm) signatures capture cumulative lifestyle exposures and biological aging. This prospective study evaluated whether DNAm-based scores and epigenetic aging clocks are associated with clinical outcomes and mortality in a multinational cohort of patients with heart failure (HF). Methods: We studied 2,594 patients with HF from 40 countries in the Global Congestive Heart Failure (G-CHF) registry with whole-blood DNAm data. Fifteen published DNAm-based scores and epigenetic aging clocks reflecting lifestyle, environmental and physiological exposures, inflammation, frailty, mortality risk, and biological aging were derived. Associations with HF hospitalization, cardiovascular death, and all-cause death were assessed using multivariable Cox regression adjusted for age, sex, ancestry, the MAGGIC risk score, and NT-proBNP. Incremental prognostic value was compared to MAGGIC score and NT-proBNP. Extreme DNAm profiles were defined as scores or clocks exceeding {+/-}1.5 standard deviations (s.d.) from the population mean. Results: Mean age was 62.7{+/-}14.0 years, 66.2% were male, and mean left ventricular ejection fraction was 40.1{+/-}14.1%. During a median follow-up of 3.0 years, 338 patients were hospitalized for HF, 349 died from cardiovascular causes, and 565 died from any cause. Higher epigenetic age and DNAm scores for CRP, frailty, and mortality were associated with increased risk, whereas higher diet-related DNAm scores were inversely associated. For all-cause death, adjusted hazard ratios per 1-s.d. were 1.36 (95% CI, 1.24-1.50) for GrimAge, 1.27 (95% CI, 1.17-1.38) for the DNAm score for CRP, 1.44 (95% CI, 1.28-1.63) for the DNAm score for frailty, and 1.48 (95% CI, 1.32-1.65) for the DNAm score for mortality, compared with 0.81 (95% CI, 0.75-0.88) and 0.86 (95% CI, 0.79-0.94) for the DNAm scores for Alternative Healthy Eating Index and Mediterranean Diet Score. These patterns were directionally consistent for cardiovascular death and weaker for HF hospitalization and were more pronounced among patients with lower clinical risk (MAGGIC<17, Pinteraction<0.05), particularly for all-cause death. Patients with 4-5 extreme-high DNAm scores or clocks had more than twice the risk of death (HR, 2.27; 95% CI, 1.65-3.13). Conclusions: DNAm-based scores and epigenetic aging clocks reflect multiple dimensions of biological vulnerability in HF and are associated with clinical outcomes and mortality beyond clinical risk factors.
P. Meyre, M. Chong, E. Shemesh et al.· medRxiv· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
