Inflammation mediates the Pace of aging based on DNA methylation on mortality from NHANES 1999-2002: a national prospective cohort study.

Assessing Differences Between Epigenetic versus Chronologic Age for Cardiovascular Risk Assessments in the United States.

Background: Epigenetic clocks derived from DNA methylation estimate biological aging and have been associated with cardiometabolic death. We evaluated whether substituting epigenetic age for chronologic age within PREVENT altered associations with all-cause and cardiovascular mortality or improved discrimination. Methods: We analyzed National Health and Nutrition Examination Survey 1999-2002 data linked to National Death Index follow-up through December 31, 2019. Adults aged 50-79 years without baseline cardiovascular disease and with DNA methylation data were included. PREVENT is a primary-prevention framework incorporating demographic, cardiometabolic, renal, and treatment factors. Exposures were PREVENT estimates calculated using chronologic age or 8 epigenetic ages substituted for chronologic age, with other inputs unchanged. Survey weighted Cox models estimated associations with all-cause and cardiovascular mortality per 5-percentage-point higher predicted risk. Weighted Harrell C statistics assessed discrimination; 95% CIs were obtained by bootstrap resampling. Results: The cohort included 1,516 participants (weighted mean age, 60.3 years; SD, 8.0) with a mean follow-up of 17.35 years; 507 participants died, including 140 cardiovascular deaths. Each 5-percentage-point increase in chronologic PREVENT risk was associated with all-cause mortality (HR, 1.57; 95% CI, 1.45-1.70) and cardiovascular mortality (HR, 1.66; 95% CI, 1.501.84). Biologic variants showed similar associations for all-cause mortality (HR range, 1.391.57) and cardiovascular mortality (HR range, 1.47-1.67). Chronologic PREVENT showed higher discrimination for all-cause mortality (C, 0.74; 95% CI, 0.72-0.77) than biologic variants (C range, 0.66-0.73) and for cardiovascular mortality (C, 0.78; 95% CI, 0.73-0.84) than biologic variants (C range, 0.71-0.77). Conclusions: Biologic PREVENT variants were associated with mortality but did not improve discrimination compared with chronologic PREVENT, suggesting biological aging metrics may complement rather than replace chronological age in cardiovascular risk prediction.

Urinary organophosphate metabolites, DNA methylation aging, and heart disease mortality in middle-aged and older adults: an exploratory cohort study with in vitro evidence of biological plausibility

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.

Cross-Sectional and Longitudinal Association Between Biological Aging Acceleration and the Risk of Osteoarthritis: A Cohort Study From UK Biobank.

Epigenetic signatures of biological vulnerability and residual risk in heart failure

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.

Social Adversity, Systemic Inflammation, and the Ticking of the Biological Aging Clocks in Men and Women

It is found that socioeconomic adversity influences not only inflammatory pathways but also distinct biological aging processes, including metabolomic aging, and that socioeconomic adversity influences not only inflammatory pathways but also distinct biological aging processes.

Time-dependent biology of mortality in middle-aged and older adults: Distinct predictors for near- and long-term outcomes in a population-based cohort in Taiwan

Objectives Population aging is accompanied by increasing heterogeneity in health trajectories and mortality risk. We aimed to identify and compare independent predictors of 3-year and 5-year all-cause mortality in Taiwanese adults aged ≥50 years, integrating intrinsic capacity (IC), functional status, laboratory biomarkers, and genetic factors within a unified multidomain framework. Methods This study used data from the Social Environment and Biomarkers of Aging Study (SEBAS, n = 772), a population-based cohort embedded within the Taiwan Longitudinal Study of Aging. Assessments covered five IC domains, functional status, 13 comorbidities, a comprehensive biomarker panel (inflammatory, metabolic, neuroendocrine, hematologic, nutritional), and genetic markers (ApoE ε4, 5-HTTLPR). Mortality was ascertained through national death registry linkage. Predictors were identified by stepwise selection and multivariable Cox proportional hazards models. Results The mean age of participants was 65.3 years (SD 9.3), and 55.7% were men. Distinct predictor profiles emerged for near-term (3-year) and long-term (5-year) mortality. Near-term mortality was dominated by markers of acute vulnerability: low grip strength (HR 4.98, 95% CI 1.88–13.20), depressive symptoms (HR 3.42, 95% CI 1.34–8.71), and proinflammatory biomarkers including interleukin-6 and neutrophil percentage while serum albumin was protective (HR 0.13, 95% CI 0.04–0.42). Long-term mortality reflected a broader accumulation of multisystem burden: low grip strength remained predictive (HR 2.57, 95% CI 1.43–4.62), but was joined by metabolic and renal markers (HbA1c and creatinine), and immune aging indices (monocyte and lymphocyte percentages), whereas higher Instrumental Activities of Daily Living scores were protective (HR 0.78 per unit increase, 95% CI 0.65–0.94). Conclusion Mortality risk in aging adults is multidimensional and time-dependent. Near-term mortality was driven by acute physiologic vulnerability, such as nutritional depletion, muscular reserve loss, and active inflammation, whereas long-term mortality reflected cumulative metabolic, renal, and immune-aging burden. These findings supported time-horizon–specific, multidomain risk stratification in aging populations.