Accelerated epigenetic ageing in congenital heart disease: the AccelerAGE study

BACKGROUND AND AIMS: Adults with congenital heart disease tend to develop both cardiac and noncardiac age-related comorbidities earlier in life than the general population, suggesting accelerated biological ageing. Epigenetic clocks estimate biological age based on DNA methylation profiles. This study investigated whether adults with congenital heart disease display accelerated epigenetic ageing and whether the degree of age acceleration relates to disease complexity. METHODS: A total of 120 patients with congenital heart disease (age 29-50 years, 58 females) and 120 age- and sex-matched healthy controls were included. Patients were divided into simple, moderate, and complex disease complexity groups (n = 40 per group). Epigenetic age was estimated using the Horvath, Hannum, Zhang, GrimAge2, and PhenoAge clocks, whereas the pace of ageing was assessed using DunedinPACE. RESULTS: Compared to healthy controls, patients with moderate and complex congenital heart disease exhibit significant age acceleration with PhenoAge (+3.0 years, P = .019; +5.5 years, P < .001) and GrimAge2 (+2.1 years, P = .045; +2.3 years, P = .022) and a higher pace of ageing (P = .008 and P = .016, respectively). No significant differences were detected between healthy controls and patients with simple disease. CONCLUSIONS: Accelerated epigenetic ageing is observed in adults with moderate and complex congenital heart disease, while individuals with simple disease show ageing patterns comparable to healthy peers. These findings provide biological evidence of premature ageing in congenital heart disease and suggest a lifelong systemic vulnerability. Integrating biological ageing metrics into follow-up strategies may enable earlier detection of age-related complications and support interventions to preserve long-term healthspan.