Abstract / Summary
Background: Older adults are vulnerable to frailty, but the biological mechanisms are unclear. Metabolomics and proteomics may help characterize the biological basis of frailty that can be used to target future interventions. Methods: This study is a cross-sectional analysis of baseline anthropometric, metabolomic, and proteomic data collected from older adults enrolled in a 12-week prospective physical therapy intervention. Frailty was classified using a modified Cumulative Deficit Index (CDI; 37 variables) and the Fried Frailty Index (5 variables). Gait speed, grip strength, and patient-reported outcome surveys were administered. Baseline plasma was analyzed via semi-targeted metabolomics (capillary electrophoresis-mass spectrometry) and untargeted proteomics (LC-MS/MS) using the CDI-defined frailty classification. Results: Mean age was 77.1 ± 5.5 (33% female). Using the CDI, 12 participants had pre-frailty and 6 had frailty. Participants with frailty had worse gait speed (p = 0.01), instrumental activity of daily living impairments (p = 0.005), and lower physical activity (p = 0.006). Metabolomics showed nicotinamide as decreased (p = 0.0066; log2FC = −1.19; FDR correction q = 0.753). Amino acid metabolites showed strong, positive correlations with weight, but negative with gait speed. Proteomics showed 65 differentially expressed proteins by frailty status (FDR-adjusted q-value < 0.05), 53 of which also with a |log2FC| ≥ 0.6 (26 higher in participants with frailty, and 27 higher in participants with pre-frailty). Specifically, histone proteins were elevated in participants with frailty. In exploratory, descriptive correlation analyses, patterns of association between protein levels and physical function measures differed between pre-frail and frail status, including apparent shifts in correlation direction and magnitude, most notably for gait speed and dietary scores. Conclusions: Histone proteins and nicotinamide may warrant further investigation as candidate exploratory markers in relation to frailty. However, our cross-sectional pilot study is unable to accurately delineate a definitive mechanistic association. Moreover, future studies should investigate these biomarkers’ roles in frailty progression. Our findings suggest a potential signal, yet in light of the small sample size, should not be interpreted as causal in nature.