Simone Scarlata, Alessio Marinelli, Panaiotis Finamore, Vitaliano Nicola Quaranta, Giulia Amoroso, Alessandra Tomasello, Claudio Sorino, Giovanna Elisiana Carpagnano, Nicola Scichilone, Silvano Dragonieri
Background: Chronic obstructive pulmonary disease (COPD) disproportionately affects older adults. While targeted biologic therapies have shown efficacy in type 2 eosinophilic endotypes, elderly patients remain underrepresented in pivotal clinical trials. This narrative review examines the pathophysiological rationale, efficacy data, and unique geriatric challenges of biologic therapies in older adults. Methods: A literature search was conducted in PubMed and Scopus for phase II and III randomized controlled trials (RCTs) and observational studies evaluating biologic agents (anti-IL-5, anti-IL-4/IL-13, and anti-alarmins) in COPD, focusing on populations aged ≥ 65 years, comorbidities, and frailty. Discussion: Phase III data for dupilumab and mepolizumab indicate significant reductions in annualized exacerbations in patients with blood eosinophils ≥ 300 cells/μL. However, the mean age in the landmark trials (65 years) is a decade lower than the real-world average. Age-related immune remodeling-specifically immunosenescence and inflammaging-coexists with disease-specific pathways, potentially altering therapeutic responses. Furthermore, clinical trials systematically exclude older individuals with severe multimorbidity, physical frailty, cognitive impairment, and malnutrition. Conclusions: Biologics provide a precise, mechanism-based approach, yet evidence in the oldest-old remains limited. Future management should utilize the treatable traits framework, shifting selection criteria from chronological age to biological age metrics, including frailty status and functional reserve.