Development and internal validation of an age less-dependent frailty score in the cardiovascular health study

Frailty is a proxy for biologic aging that confers risk independently of chronologic age. Most frailty indices correlate strongly with chronologic age, making independent features of biologic aging challenging to identify.

We aimed to create a novel Age Less-Dependent Frailty (AGELESS) Score less-associated with chronologic age than the Fried frailty phenotype. Among Cardiovascular Health Study participants with available echocardiographic data, we identified demographic, clinical, serologic, and echocardiographic variables more correlated with a continuous version of the Fried frailty phenotype than age, then used LASSO regression for variable selection. In a 25% leave-out sample, we internally validated the score's association with age-adjusted all-cause and cardiovascular mortality and compared model characteristics with the Fried frailty phenotype.

In 4,029 individuals (mean age 72 ± 5.0 years, 59.6% female), serum cystatin C, depression, diabetes, educational attainment, forced expiratory volume in 1 s, and income were more associated with frailty than age and selected for inclusion in the AGELESS Score. Adjusted for age, individuals in the highest vs. lowest quartiles of the AGELESS Score had a higher risk of all-cause (HR: 1.44, 95% CI: 1.17-1.79, p < 0.001) and CV death (HR: 1.64, 95% CI: 1.43-1.87, p = 0.002). The AGELESS Score was less correlated with age (AGELESS r = 0.23, 95% CI: 0.16-0.30; Fried r = 0.28, 95% CI: 0.21-0.34; p-value for comparison of correlations < 0.001) and more closely associated with all-cause and CV mortality within each age quartile than the Fried frailty phenotype.

We derived and internally validated a novel frailty score that is less associated with chronologic age than existing indices and predicts mortality within age strata better than the existing reference standard for phenotypic frailty. This score could help identify high-risk patients with frailty across the age spectrum and may provide insights into mechanisms of biologic aging.