Abstract
Leukocyte telomere length (LTL) is a widely studied biomarker of biological aging, reflecting cumulative cellular damage beyond chronological age. However, its prognostic relevance in clinically complex populations such as hospitalized older adults remains uncertain. In this prospective observational study, 872 patients aged ≥ 65 years admitted to acute care wards of IRCCS INRCA within the Report-AGE cohort were included. LTL was measured by quantitative real-time PCR and expressed as age-adjusted residuals derived from an external reference population. The primary outcome was 10-year all-cause mortality. Associations between LTL residuals and mortality were assessed using Cox proportional hazards models, both as continuous variables and using a data-driven cut-point. Multivariable models adjusted for demographic characteristics, comorbidity burden, laboratory parameters, and polypharmacy were used. Effect modification by frailty was evaluated through interaction and stratified analyses. Over a median follow-up of 126.8 months, 713 patients died. Shorter age-adjusted LTL was associated with increased mortality risk in univariable analysis (HR per 1 SD decrease = 1.10, 95% CI 1.02–1.19; p = 0.012). When dichotomized using an optimal cut-point, patients with shorter-than-expected telomeres exhibited significantly higher mortality (adjusted HR = 1.30, 95% CI 1.05–1.60; p = 0.016), regardless of clinical and laboratory covariates. A significant interaction with frailty was observed ( p for interaction = 0.031), with the association between LTL and mortality being evident among patients without frailty. Age-adjusted LTL provides independent prognostic information in hospitalized older adults and may reflect biologically meaningful heterogeneity associated with aging, particularly among individuals without frailty.