Baseline levels of amino acid metabolites are associated with clinical outcomes in older persons

Background Alterations of serum amino acid levels have been associated with cardiovascular aging. However, the prognostic value of serum amino acid profiling on predicting future clinical outcomes in older persons is unknown. Methods Community adults without cardiovascular disease at baseline, underwent serum metabolomics profiling that quantitated 17 amino acid metabolites, and simultaneous cardiac evaluation. Prospective clinical outcomes were tracked over 5 years. Study outcome was a composite of all-cause mortality and hospitalization. Baseline characteristics, medical history, and amino acid levels were compared across outcome groups using t-tests or chi-square tests. Cox proportional hazards models and multivariable models were used to examine associations between metabolites and clinical outcomes. The model demonstrated moderate discrimination (Concordance = 0.661) and good calibration across time points (1-5 years). The likelihood ratio test confirmed overall model significance (p = 1e-05). Schoenfeld residual tests indicated no violations of the proportional hazards assumption (GLOBAL p = 0.69), supporting the validity of the model for predicting composite outcomes. Results A total of 634 participants (mean age 62.93±13.21 years) were included in the analysis. During a follow-up period of 5.12±0.04 years, 109 participants reached the primary composite outcome. Significant differences were observed in alanine (514.73±125.28 vs. 475.04±129.88, uM, p=0.004), proline (238.34±81.82 vs. 222.64±70.78, uM, p=0.041), age (66.73±11.19 vs. 62.14±13.46, years, p=0.001), systolic blood pressure (142.09±35.25 vs. 136.06±20.63, mmHg p=0.016), and alcohol intake (17.4% vs. 8.60%, p=0.009) between the groups with and without the composite outcome. After multivariable model adjustment, aspartic acid (HR=1.042, 95% CI 1.005-1.080), alanine (HR=1.003, 95% CI 1.001-1.005), age (HR=1.021, 95% CI 1.002-1.041), and alcohol intake (HR=1.996, 95% CI 1.170, 3.407) were associated with increased risks, while glutamic acid (HR=0.987, 95% CI 0.977-0.997) and serine (HR=0.990, 95% CI 0.981-0.998) demonstrated protective effects (Figure 1 and 2). Conclusions This study highlights significant associations between specific serum amino acids and major clinical outcomes in an older adult population with cardiac aging. Elevated aspartic acid and alanine levels were linked to increased risk, while glutamic acid and serine exhibited protective effects. These findings underscore the importance of nitrogen-related pathways in influencing clinical outcomes, particularly the balance between aspartic acid and glutamic acid which are key mediators in major nitrogen transfer reactions. Amino acid metabolomics may serve as valuable biomarkers for risk stratification and potential therapeutic targets in aging populations. Further research is needed to explore the underlying mechanisms, including the role of nitrogen metabolism and its interplay with cardiac function.Normalized radar map of amino acids Forest plot of Cox regression predictors