Frailty before chronic disease: multisystem physiological differences in middle-aged adults from the UK Biobank.

Frailty, defined as increased vulnerability to stressors and impaired recovery of homeostasis, poses a major health challenge among older and multimorbid adults. Frailty is also observed in middle-aged and disease-free adults, though evidence remains scarce. Understanding the physiological characteristics of frail individuals free of chronic diseases may inform about the underlying mechanisms of frailty and its clinical management. We assessed frailty in a large disease-free middle-aged cohort and examined the associations of markers of physiological function with frailty. We analyzed data from 117,163 middle-aged adults (mean age 53.9 ± 8.0 years) free of known chronic conditions from the UK Biobank. Associations between frailty status (robust, prefrail, frail; defined using the Fried Frailty Phenotype) and 29 physiological markers were examined using multinomial logistic regression adjusted for sociodemographic and lifestyle factors. Overall, 1,293 (1.1%) participants were frail and 38,401 (32.8%) prefrail. Anthropometric measures (body fat % waist-to-hip ratio), triglycerides, some markers of hepatic (gamma-glutamyl transferase, alkaline phosphatase) and renal function (cystatin C), glucose metabolism (HbA1c), inflammation (hsCRP), and white blood cell count including leukocyte and neutrophil count and the neutrophil-to-lymphocyte ratio were directly associated with frailty. In contrast, blood pressure, lung function markers (FEV1, FVC), other hepatic (aspartate aminotransferase, bilirubin) and renal markers (creatinine and creatinine-to-cystatin C ratio), and the endocrine marker IGF-1 were inversely associated with frailty. Associations were generally similar but weaker for prefrailty. Frailty in disease-free middle-aged adults was associated with multisystem physiological alterations resembling those observed in older and multimorbid populations, suggesting early physiological dysregulation preceding clinically manifest chronic disease.