Microbiome-Linked Metabolic Architecture of Accelerated Biological Aging in Humans

Biological aging is a major determinant of frailty, functional decline, and vulnerability to age-related diseases; however, its upstream metabolic and inflammatory signatures remain incompletely understood. We investigated biological aging using an integrated multi-omics approach in a clinically enriched human cohort. In this prospective study, 120 patients with adult spinal deformity (ASD) and 480 age- and sex-matched healthy controls were included for comparison of PhenoAge. Within the ASD cohort, high-resolution plasma metabolomics and targeted proteomics were performed to characterize metabolic and inflammatory correlates of biological aging. A composite trimethylamine N-oxide (TMAO) Pathway Index (TPI) was constructed using standardized methylamine-related metabolites. Biological age was significantly elevated in ASD compared with matched controls. Within the ASD cohort, metabolomic profiling revealed enrichment of methylamine-related and glycation-associated metabolites among the strongest correlations of PhenoAge. The TPI showed a strong, age-independent, near-linear association with PhenoAge. In sensitivity analyses adjusted for age, sex, BMI, smoking status, and eGFR, this association remained significant (β = 2.92, 95% CI 0.74-5.10, p = 0.009). Targeted proteomic analyses showed that tumor necrosis factor-α was selectively associated with both PhenoAge and the TPI, whereas associations with interleukin-1β, interleukin-6, and adiponectin were limited. Higher PhenoAge was also associated with reduced physical performance, increased frailty, and impaired health-related quality of life. These findings support an exploratory, hypothesis-generating framework in which methylamine-related metabolism and chronic inflammatory signaling are associated with biological aging in ASD. Because of the cross-sectional design, these results should be interpreted as associative rather than causal.