Accelerated Biological Aging in Cholestatic Liver Disease: Telomere Attrition and Association With Disease Severity

BACKGROUND: Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are rare, chronic cholestatic liver diseases with heterogeneous progression and limited biomarkers of disease biology. Epigenetic age acceleration has been demonstrated in PSC and PBC, suggesting accelerated biological aging. DNA methylation-derived telomere length (DNAmTL) reflects replicative aging and cellular turnover, but its role in PSC and PBC remains unclear. We aimed to evaluate DNAmTL in PSC and PBC and its association with disease severity. METHODS: We analysed and compared DNAmTL and age-adjusted DNAmTL among patients with PSC (n = 474) versus PSC controls (n = 484) and patients with PBC (n = 291) versus PBC controls (n = 291). Associations with clinical outcomes were assessed using nonparametric tests and multivariable logistic regression models. Correlations with primary sclerosing cholangitis Risk Estimate Tool (PREsTO) score and epigenetic age acceleration (AgeAccelGrim) were evaluated using linear regression. RESULTS: Patients with PSC demonstrated significantly shorter age-adjusted DNAmTL compared with controls (median -0.036 vs. 0.016, p < 0.001). Patients with PBC also exhibited reduced DNAmTL relative to controls (median 6.814 vs. 6.885, p < 0.001). Within PSC, shorter DNAmTL was associated with cirrhosis (OR 0.21, 95% CI 0.06-0.69, p = 0.013) and advanced disease (OR 0.20, 95% CI 0.06-0.67, p = 0.009). Shorter DNAmTL was also observed in hepatic decompensation and hepatobiliary malignancy, including cholangiocarcinoma. DNAmTL inversely correlated with PReSTO score (p < 0.001). DNAmTL was strongly inversely correlated with AgeAccelGrim in both PSC and PBC (p < 0.001). CONCLUSION: Cholestatic liver diseases are associated with shortened DNAmTL, which independently correlates with disease severity in PSC. Together with epigenetic age acceleration, these findings support a model of accelerated biological aging in PSC and PBC characterized by converging signatures of accelerated biological aging that may contribute to progressive biliary injury and fibrosis.