Relative Melatonergic Status and Systemic Inflammatory, Oxidative, and Biological Aging Burden in Adults: An Exploratory Cross-Sectional Biomarker Analysis

Background/objectives: Melatonin has circadian, antioxidant, mitochondrial, and immunomodulatory functions, but human data linking relative melatonergic status to coordinated systemic biomarker burden remain limited. We examined this association and tested its internal robustness to alternative score construction, outlier handling, and missing-data assumptions. Methods: We performed an adult-only cross-sectional secondary analysis of a deidentified biomarker dataset. Of 322 source records, six participants younger than 18 years and two records without age were excluded, yielding 314 adults. Plasma melatonin and 24 h urinary aMT6s were converted to within-cohort rank percentiles and averaged to form a relative melatonergic-axis score. Equal-weight z-score composites represented inflammation, oxidative damage, antioxidant deficit, and biological aging/biological injury; their mean was the integrated systemic biomarker-burden score. Analyses included Kruskal–Wallis tests; Spearman correlations with bootstrap confidence intervals; standardized regression adjusted for age, sex, and BMI; robust covariance estimates; principal component analysis (PCA), winsorization, leave-one-domain/marker-out analyses, and missing-BMI sensitivity models. Results: The lower, intermediate, and higher relative melatonergic tertiles included 105, 104, and 105 adults, respectively. The melatonergic-axis score correlated inversely with integrated systemic burden (Spearman ρ = −0.944; 5000-resample bootstrap 95% CI, −0.953 to −0.931; p < 0.001). In age-, sex-, and BMI-adjusted complete-case models (N = 250), each 1 SD higher axis score was associated with a 0.95 SD lower integrated burden (β = −0.949; HC3 95% CI, −0.983 to −0.915; p < 0.001). Results were similar for separate plasma melatonin and aMT6s models, winsorized composites, a PCA-derived score (PC1 explained 75.5% of marker variance; ρ = −0.947), leave-one-domain/marker-out analyses, and missing-BMI sensitivity models. Conclusions: Lower relative melatonergic status was associated with a highly coordinated adverse systemic biomarker pattern. The exceptional magnitude of the association requires audit of primary assay provenance and independent external replication. Because cancer, microbiome, and liquid biopsy endpoints were not measured, oncology implications remain untested prospective hypotheses.