Aging (Albany NY). 2025 Jul 3;17. doi: 10.18632/aging.206275. Online ahead of print.ABSTRACTFrailty is associated with respiratory exacerbations and mortality in individuals with Chronic Obstructive Pulmonary Disease (COPD). Among those with a smoking history and normal spirometry, frailty's association with respiratory outcomes is less defined. COPDGene is a cohort study of individuals aged 45-80 with a minimum 10 pack-year smoking history. A modified Fried Frailty Phenotype was performed at 10-year follow-up; participants were categorized as frail, prefrail, or robust. Primary outcomes were respiratory exacerbations, epigenetic pace of aging, and all-cause mortality. Among 2665 participants, 401 (15%) were frail and 1352 (51%) were prefrail. Adjusting for smoking and lung function, frailty was associated with prospective respiratory exacerbation rate (IRR 3.4, 95% CI 2.4-4.8), severe exacerbations (OR 2.8(1.8-4.2)), and frequent exacerbations (OR 5.5(3.2-9.3)). Prefrailty was also associated with exacerbation outcomes (rate IRR 1.8(1.4-2.3); severe OR 1.6(1.1-2.2); frequent OR 2.6(1.7-4.1)). Frailty and prefrailty were associated with increased all-cause mortality (AHR: frailty 4.5(2.4-8.5); prefrailty 2.5(1.5-4.2)). All frailty (and most prefrailty) findings persisted in those with normal spirometry. Baseline DunedinPACE of aging was associated with prospective frailty at 10-year follow-up. Frailty associated with respiratory exacerbations and mortality; findings persisted among individuals with normal spirometry, highlighting the relevance of evaluating for frailty in people with a history of smoking.PMID:40622758 | DOI:10.18632/aging.206275