Frailty before disease onset: risk of mortality and chronic conditions in disease-free middle-aged adults

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Frailty, defined by multisystem physiological decline and heightened vulnerability to stressors, is typically associated with aging and chronic disease. However, its relevance in apparently healthy individuals remains poorly understood. Identifying frailty in this population could inform primary prevention, as these individuals often remain outside healthcare systems. We investigated the association between frailty and incident chronic conditions and mortality in middle-aged adults free of chronic disease at baseline. Using UK Biobank data, we included 183,783 participants (53.6% female; median age 54 years) without chronic conditions. Frailty was assessed via the Fried frailty phenotype. Cox regression and multi-state models, adjusted for sociodemographic and lifestyle factors, analyzed associations with all-cause and cause-specific mortality, and with overall and organ system-specific incident chronic conditions. At baseline, 1.4% of participants were frail and 34.7% prefrail. Over a median follow-up of 13.8 years, mortality was 9.1% in frail versus 4.1% in robust (non-frail, fit) individuals, and 60.5% versus 48.2% developed at least one chronic condition. Frailty was associated with higher hazards of all-cause mortality (HR 1.92, 95% CI 1.68-2.20) and incident chronic conditions (HR 1.34, 95% CI 1.27-1.41), as well as increased risk of death following disease onset. Associations persisted after excluding events within 10 years of follow-up and were observed across multiple disease categories, including circulatory diseases, independent of key biological risk markers. Similar patterns were noted for prefrailty. Frailty identifies a subgroup of apparently healthy middle-aged adults at increased long-term risk of mortality and chronic disease, suggesting its potential as an early, actionable marker for prevention strategies.

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