A Metabolite Score of Unintentional Weight Loss Explained a Substantial Proportion of Associated Mortality and...

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.