Metabolomic Profiling of Long-Lived Individuals Reveals a Distinct Subgroup with Cardiovascular Disease and Elevated Butyric Acid Derivatives

<b>Background/Objectives</b><b>:</b> Understanding metabolic adaptations in long-livers provides critical insights into the biochemical mechanisms underlying extreme longevity. While many long-livers maintain metabolic stability, others exhibit significant metabolic alterations, potentially linked to age-related diseases. This study aims to identify distinct metabolic signatures in long-livers and their associations with clinical outcomes, particularly cardiovascular disease. <b>Methods:</b> We analyzed serum samples from 53 oldest long-livers (mean age 98.2 ± 2 years) using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify metabolic alterations and gathered clinical data to link the detected metabolic changes with phenotypes. <b>Results:</b> Using Welch's <i>t</i>-test with Benjamini-Hochberg FDR correction (q < 0.01, |log2FC| > 2), we identified 15 significantly altered metabolites distinguishing a subgroup of 6 long-livers from 47 metabolically stable individuals. This metabolically altered subgroup exhibited striking elevations in key metabolites, including L-serine (log2FC = 8.05, >250-fold increase, q = 1.26 × 10^-8), D-galactose (log2FC = 6.86, 116-fold, q = 8.87 × 10^-7), butyric acid (log2FC = 6.24, 75-fold, q = 9.79 × 10^-5), and choline (log2FC = 6.11, ~69-fold, q = 5.45 × 10^-7), with enrichment in the butyric acid metabolism pathway. Post hoc power analysis confirmed >80% power for all significant metabolites with very large effect sizes (Cohen's d > 2.0). <b>Conclusions:</b> Our findings reveal substantial metabolic heterogeneity among long-livers, with a distinct subgroup exhibiting profound metabolic alterations and clinical features associated with cardiovascular and systemic disease. These results highlight that the butyric acid pathway may contribute to age-related disease survival in extreme aging.