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Cited by 44Tryptophan and brain disordersMetabolomics and Mass Spectrometry StudiesAdipokines, Inflammation, and Metabolic Diseases

Metabolites Associated With Circulating Interleukin-6 in Older Adults

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Lustgarten, Michael S., Fielding, Roger A.·2016·The Journals of Gerontology Series A: Biological Sciences and Medical Sciences
DOI 10.1093/gerona/glw039PMC PMC6279159
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Abstract

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, γ-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 ω-oxidation (adipate, 8-hydroxyoctanoate, azelate, sebacate, undecanedioate, γ-CEHC), and peroxisome proliferator activated receptor-alpha (PPAR-α) 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 ω-oxidation and PPAR-α activation may be related to decreased inflammation in older adults. Key Words: Inflammation-Metabolomics-AgingInterleukin-6 (IL-6) is a pro-inflammatory cytokine that is secreted from activated monocytes, macrophages, fibroblasts, adipocytes, myocytes, and endothelial cells in response to various stimuli, including bacterial endotoxins, physical exercise, and oxidative stress (1).IL-6 levels are often undetectable in young individuals but increase with advancing age (2).In older adults, elevated levels of IL-6 are associated with decreased physical function, frailty, disability, cognitive decline, obesity, diabetes, cardiovascular disease, cancer, and an increased mortality risk (3-11).Because older adults (70+ years) are the fastest growing subpopulation in the world (12), the development of an improved understanding about mechanisms related to circulating levels of IL-6 will be important for addressing the public health priority of healthy aging.One approach that can be used to elucidate mechanisms related to circulating levels of IL-6 is mass spectrometry (MS)-based metabolomics, which (when an untargeted approach is used) aims to characterize and quantify all of the metabolites in a biological sample, thereby providing an analytical description of complex metabolic

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  • In the serum of healthy adults, IL-6 is normally lower than 2 pg/mL or undetectable, and serum IL-6 gradually increases with advancing age.

    “In the serum of healthy adults, IL-6 is normally lower than 2 pg/mL or undetectable, while a gradual increment of serum IL-6 amounts with advancing ages (Fig. 3) [39, 40].”

    From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [40]

    The introductory passage in the paper’s Abstract section says IL-6 is often undetectable in young individuals and increases with advancing age. The Results report a median of 1.9 pg/mL in a cohort of overweight older adults, but do not establish that serum IL-6 is normally below 2 pg/mL in healthy adults. Page numbers were not available in our copy. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Lustgarten, M. S., & Fielding, R. A.
Affiliations
Tufts University (US)
Corresponding author
Fielding, Roger A.
ORCID
Venue
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences
Publisher
Oxford University Press (OUP)
Published
2016-03-14
Volume
72
Issue
9
Pages
glw039
ISSN
  • 1079-5006 (ISSN-L)
  • 1758-535X
DOI
10.1093/gerona/glw039
PMC
PMC6279159
OpenAlex
W2301559018
Cited by
44
References
4
Citations by year
2026: 5 · 2025: 4 · 2024: 8 · 2023: 2 · 2022: 3 · 2021: 7 · 2020: 6 · 2019: 5 · 2018: 2 · 2017: 2
FWCI
1.02
Type
journal article
Language
en
Open access
Locations
  • The Journals of Gerontology Series A (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
U.S. Department of Agriculture
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
interleukin-6, older adults, serum metabolites, tryptophan metabolism, kynurenine, indoxyl sulfate, aryl hydrocarbon receptor, CYP1A, PPARα, inflammation, infectious burden, bilirubin, N-formylmethionine, uridine
MeSH terms
Aged, Enzyme-Linked Immunosorbent Assay, Female, Humans, Inflammation, Male, Biomarkers, Interleukin-6, Metabolomics, Sedentary Behavior

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