A Metabolite Score of Unintentional Weight Loss Explained a Substantial Proportion of Associated Mortality and Mobility Limitation Risk in a Biracial Older Cohort

Unintentional weight loss (UWL) is related to mortality and mobility limitation. Here, we aimed to develop a metabolite‐based score for UWL and evaluate its prediction performance and explanation value for UWL‐related health outcomes. Participants from the Health, Aging and Body Composition (Health ABC) study with available metabolomics and valid follow‐ups were included ( N = 2286). First, in the derivation group ( N = 1200), 27 of the 77 metabolites associated with incident UWL (> 3% annual UWL vs. weight stable) were selected by LASSO‐logistic regression. The UWL metabolite score was calculated as a weighted sum of these 27 standardized metabolites, with higher scores indicating greater UWL risk. We then examined the standardized UWL metabolite score against all‐cause mortality and incident mobility limitation using Cox regression. Overall, older adults with a one‐SD higher UWL metabolite score had higher risks for mortality (1.44 [1.36, 1.52]) and mobility limitation (1.23 [1.15, 1.32]). The score also improved mortality prediction beyond traditional risk factors. Similar results were observed in the hold‐out test group ( n = 1086). Furthermore, this score explained 28% of the UWL‐mortality relationship and 22% of the UWL‐mobility limitation relationship beyond lifestyle and medical history, respectively. The score also predicted higher mortality and mobility limitation among those with intentional weight loss and weight gain, demonstrating a good Out‐Of‐Distribution generalizability. This metabolomic characterization of UWL is predictive of key aging outcomes in the Health ABC participants and captures a substantial portion of the mortality and mobility limitation risks related to unintentional weight loss, further validating the importance of these metabolite signatures.