Social experiences and mortality risk: mediating roles of epigenetic aging, allostatic load, and health status

Childhood trauma, accelerated biological aging and chronic pain across two population cohorts

Sensory impairment, epigenetic ageing, and later-life functional decline and mortality in older adults.

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.

Accelerated biological aging: the role of chronic inflammation, weathering and novel therapeutic strategies

Biological aging is a gradual, multisystem process characterized by progressive functional decline, diminished physiological resilience, and increased susceptibility to chronic diseases. Growing evidence suggests that persistent exposure to adverse social environments, chronic psychological stress, and socioeconomic disadvantage can accelerate biological aging by altering age-related biomarkers and stress-response pathways. The weathering hypothesis provides a framework to explain how the cumulative burden of psychosocial adversity becomes biologically embedded, resulting in physiological wear and tear that hastens age-related deterioration over time. A central mechanism underlying this process is chronic low-grade inflammation, which contributes to the pathogenesis of numerous age-related conditions, including cancer and neurodegenerative diseases (NDDs). These disorders are highly prevalent among Caribbean Hispanics, a population disproportionately affected by social disadvantages and rapid population aging. Recent advances in the biology of inflammation and cellular senescence have generated interest in therapeutic strategies aimed at modulating fundamental mechanisms of aging. Emerging approaches, including senolytics, anti-inflammatory agents, and non-coding RNA–based interventions, offer promising opportunities for precision medicine; however, RNA-based therapies remain largely experimental, and their clinical translation to address stress-related aging and health disparities has yet to be established. In this review, we examine the interplay between weathering and inflammation in shaping biological aging and discuss the potential of innovative precision medicine approaches to mitigate age-related decline and reduce health disparities in vulnerable populations.

Social determinants of health and biological embedding: From the social gradient to epigenetics in the DOHaD context.

Current evidence shows that social and environmental conditions present from the earliest stages of life can influence health and disease trajectories. From the perspective of the DOHaD (developmental origins of health and disease) paradigm, the social determinants of health interact with nutritional, environmental, toxic, and psychosocial factors during periods of high biological plasticity, especially during the first 1000 days of life, modulating developmental programming processes. This view is supported by the social gradient in health, which shows a progressive worsening of morbidity and mortality as socioeconomic status declines. Based on these observations, the biological embedding hypothesis and social epigenetics have helped us understand how early-life experiences can influence human biology, providing evidence of molecular mechanisms linked to changes in DNA methylation patterns.

Accelerated Epigenetic Aging in Diabetes: Socio-Biological Pathways of Health Inequity.

The results warrant validation studies to better understand socio-glucometabolic pathways shared by epigenetic aging processes and to inform early risk stratification among at-risk older women for disease prevention and reduced racial health inequity.