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Microbiome-Linked Metabolic Architecture of Accelerated Biological Aging in Humans
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DOI：10.14336/AD.2026.0237.png)
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Abstract
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Biological aging is a major determinant of frailty, functional decline, and vulnerability to agerelated 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 ageand sexmatched 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 (beta = 2.92, 95% CI 0.74-5.10, p = 0.009). Targeted proteomic analyses showed that tumor necrosis factor-alpha was selectively associated with both PhenoAge and the TPI, whereas associations with interleukin-1 beta, 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.
Keywords:
biological aging
gut microbiome
metabolomics
proteomics
trimethylamine n-oxide
inflammaging
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