Beyond Chronological Age: A Multi-Domain Framework for Integrating Epigenetic Biological Age into Preoperative Surgical Recovery Risk Stratification

This manuscript proposes EpiSurg, a novel preoperative risk calculator that integrates DNA methylation-based biological age metrics: GrimAge, PhenoAge, and DunedinPACE, alongside nutritional status, physiological frailty, comorbidity burden, wound and surgical history, and operative context into a composite risk score. The framework addresses a fundamental gap in existing surgical risk tools, none of which incorporate biological age despite growing evidence that epigenetic age acceleration predicts adverse outcomes more powerfully than chronological age alone. EpiSurg operates in two configurations: Clinical Mode, a five-domain composite requiring no molecular data that outperforms the ACS NSQIP Surgical Risk Calculator on frailty assessment, nutritional biomarkers, and wound-specific history; and Research Mode, which activates the full six-domain composite using preoperative methylation profiling. A distinguishing feature is the framework's individualized prehabilitation output, which maps high-scoring domains to targeted preoperative interventions rather than generating a risk estimate alone. Domain weights are presented as provisional expert-derived estimates pending prospective validation, with a staged two-tier validation roadmap, retrospective NSQIP-based Clinical Mode validation followed by a prospective epigenetic cohort study, designed to be feasible within current academic surgical infrastructure.