Epigenetic age acceleration is associated with metabolic syndrome and vascular stiffness in adults with overweight and obesity: an observational cohort study

Obesity is associated with various age-related diseases, including diabetes, atherosclerosis, and cancer, and it has been proposed that obesity accelerates biological aging. Epigenetic age acceleration (EAA), derived from DNA methylation-based epigenetic clocks, is a biomarker of biological aging, lifespan, and disease. We assessed whether metabolic and atherosclerotic complications are associated with EAA in individuals with overweight or obesity, and we explored potential inflammatory and metabolic underlying pathways. Cross-sectional observational cohort study in 299 individuals (median age 67.0 years) with a BMI > 27 kg/m 2 . We assessed vascular stiffness with pulse wave velocity (PWV), and carotid atherosclerosis by ultrasound. We calculated associations between EAA and MetS, vascular stiffness, and atherosclerosis. We explored underlying mechanisms by measuring circulating cytokines and adipokines, immune cell profiles, and adipose tissue (AT) inflammation. MetS presence was strongly associated with EAA according to the GrimAge and GrimAge2 clocks. EAA was also associated with circulating cytokine concentrations, and circulating monocytes, but not with AT inflammation. The association between MetS and EAA was partly mediated by reduced circulating adiponectin and increased monocyte counts. EAA was associated with increased PWV, intima media thickness, and carotid atherosclerosis, but for these latter two associations significance disappeared after adjustment of classical cardiovascular risk factors. Findings were replicated in an independent cohort of 563 people living with HIV with a BMI > 27 kg/m 2 . These findings suggest that metabolic complications of obesity and systemic inflammation are associated with EAA, highlighting metabolic dysfunction as a potential contributor to premature biological aging in obesity, and EAA as a biomarker for metabolic and vascular complications in individuals with obesity. A schematic overview of the project