Metabolites Associated With Circulating Interleukin-6 in Older Adults

Background: Circulating levels of the pro-inflammatory cytokine interleukin-6 (IL-6) levels are elevated in older adults, but mechanisms are unclear. In the current study, we used an untargeted metabolomic approach to develop an improved understanding about mechanisms related to circulating IL-6 in older adults. Methods: Serum IL-6 values were log-transformed to normalize its distribution. Multivariable-adjusted linear regression was used to examine the association between 324 serum metabolites with log IL-6. Backward elimination linear regression was used to develop a metabolite predictor set representative of log IL-6. Results: Thirty-six metabolites were significantly associated (p < 0.05 and q < 0.30) with log IL-6 in 73 older adults (average age, 78 years). Metabolites related to tryptophan metabolism (kynurenine, 3-indoxyl sulfate, indoleacetate, indolepropionate, C-glycosyltryptophan), infectious burden (C-glycosyltryptophan, N-6-carbamoylthreonyladenosine, 1-methylurate, N-formylmethionine, N-1-methyladenosine, 3-indoxyl sulfate, bilirubin (E, E), indoleacetate, gamma-CEHC, N-acetylneuraminate), aryl hydrocarbon receptor activation and cytochrome P450 (CYP) 1A expression (kynurenine, 3-indoxyl sulfate, indoleacetate, N 6 -carbamoylthreonyladenosine, bilirubin, 1-methylurate) were positively associated, whereas metabolites related to CYP-mediated omega-oxidation (adipate, 8-hydroxyoctanoate, azelate, sebacate, undecanedioate, gamma-CEHC), and peroxisome proliferator activated receptor-alpha (PPAR-alpha) activation (13 + 9-HODE, bilirubin, 5-oxoproline, cholesterol, glycerate, uridine) were negatively associated with log IL-6. The use of backward elimination regression identified tyrosine, cysteine, uridine, bilirubin, N-formylmethionine, indoleacetate, and 3-indoxyl sulfate to collectively explain 51% of the variance inherent in log IL-6. Conclusions: These data suggest roles for tryptophan metabolism, infectious burden, activation of host defense, and detoxification through CYP1A-mediated pathways in mechanisms related to elevated inflammation, whereas CYP-mediated omega-oxidation and PPAR-alpha activation may be related to decreased inflammation in older adults.