Grim Age, Grim Prognosis: Epigenetic Aging Predicts Pancreatic Surgery Risk.

To evaluate the association of Epigenetic age acceleration (EAA), measured using the Horvath, Pheno, and Grim clocks, with overall survival (OS), postoperative complications, and failure of adjuvant chemotherapy completion in patients with resectable pancreatic ductal adenocarcinoma (PDAC). Surgical resection is the only curative option for patients with PDAC. However, perioperative morbidity remains substantial, and existing risk assessments inadequately predict postoperative complications, adjuvant chemotherapy completion, and OS. EAA measures biological aging through DNA methylation patterns and may provide insights into these outcomes. This prospective cohort study was conducted between July 2009 and May 2023, with follow-up extending to August 2024. Patients aged >18 who were scheduled for pancreatic surgery at Copenhagen University Hospital, Rigshospitalet, were included. Exclusion criteria were non-PDAC histology, non-resectable disease, salvage surgery (gastroenterostomy/hepaticojejunostomy only), or neoadjuvant chemotherapy. DNA methylation of preoperative blood samples was analyzed using the Infinium MethylationEPIC v2.0 Kit (Illumina). Among 332 patients (45% female, median age 69 y), higher preoperative Grim EAA was associated with reduced OS (hazard ratio (HR 1.12; 95% CI 1.02-1.27; P=0.024), increased severe postoperative complications (OR 1.77; 95% CI 1.16-2.68; P=0.008) and failure to complete adjuvant chemotherapy (OR 1.47; 95% CI 1.20-1.81; P<0.0001). Grim EAA may serve as a preoperative risk assessment tool for patients with resectable PDAC, potentially guiding personalized treatment. Further validation is required for clinical integration.