Epidemiology A Metabolite Score Explains Relationships of Unintentional Weight Loss with Mortality and Mobility Limitation

Abstract Unintentional weight loss (UWL) is related to mortality and functional decline. Using 77 metabolites associated with UWL risk in the Health, Aging and Body Composition participants, we investigated whether a composite metabolite score explained the relationship of UWL with mortality and mobility limitation. First, we selected 27 metabolites associated with incident UWL (>3% annual loss vs weight stable) using penalized logistic regression. Next, we created an UWL metabolite score, sum of 27 standardized metabolites weighted by their association with incident UWL, with a higher score indicating a greater potential risk for UWL. Among 2,286 participants (mean age 75, 37% Black, 51% women), those with UWL had 60% higher mortality and 25% higher hazard of mobility limitation risk after weight loss compared with weight-stable individuals, adjusting for age, race, sex, and study site. Older adults with one-SD higher UWL metabolite score had significantly higher mortality (HR = 1.44 [1.23, 1.52]) and mobility limitation risk (HR = 1.23 [1.15, 1.32]). The UWL metabolite score attenuated 39% of the relationship UWL and mortality, greater than 11% attenuated by traditional risk factors (i.e. demographics, lifestyle, and health conditions) and 16% by clinical biomarkers (cholesterol, glucose, kidney function, and inflammation biomarkers). Similarly, the UWL metabolite score attenuated 27% of the relationship between UWL and mobility limitation risk, contributing an additional 22% beyond traditional risk factors. This targeted metabolic characterization of UWL captures a substantial portion of the mortality and mobility limitation risks not explained by commonly measured health indicators, highlighting its potential value in risk assessment among older adults.