Dataset Information

Metabolites Associated With Circulating Interleukin-6 in Older Adults.

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, N6-carbamoylthreonyladenosine, 1-methylurate, N-formylmethionine, N1-methyladenosine, 3-indoxyl sulfate, bilirubin (E,E), indoleacetate, ?-CEHC, N-acetylneuraminate), aryl hydrocarbon receptor activation and cytochrome P450 (CYP) 1A expression (kynurenine, 3-indoxyl sulfate, indoleacetate, N6-carbamoylthreonyladenosine, bilirubin, 1-methylurate) were positively associated, whereas metabolites related to CYP-mediated ?-oxidation (adipate, 8-hydroxyoctanoate, azelate, sebacate, undecanedioate, ?-CEHC), and peroxisome proliferator activated receptor-alpha (PPAR-?) 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 ?-oxidation and PPAR-? activation may be related to decreased inflammation in older adults.

SUBMITTER: Lustgarten MS

PROVIDER: S-EPMC6279159 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Publications

Metabolites Associated With Circulating Interleukin-6 in Older Adults.

Lustgarten Michael S MS Fielding Roger A RA

The journals of gerontology. Series A, Biological sciences and medical sciences 20170901 9

<h4>Background</h4>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.<h4>Methods</h4>Serum IL-6 values were log-transformed to normalize its distribution. Multivariable-adjusted linear regression was used to examine the association between 324 serum ...[more]

PMID: 26975982

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Project description:Reduced skeletal muscle density in older adults is associated with insulin resistance, decreased physical function, and an increased all-cause mortality risk. To elucidate mechanisms that may underlie the maintenance of skeletal muscle density, we conducted a secondary analysis of previously published muscle composition and serum metabolomic data in 73 older adults (average age, 78y). Multivariable-adjusted linear regression was used to examine associations between 321 metabolites with muscle composition, defined as the ratio between normal density (NDM) with low density (LDM) thigh muscle cross sectional area (NDM/LDM). Sixty metabolites were significantly (p?0.05 and q<0.30) associated with NDM/LDM. Decreased renal function and the immune response have been previously linked with reduced muscle density, but the mechanisms underlying these connections are less clear. Metabolites that were significantly associated with muscle composition were then tested for their association with circulating markers of renal function (blood urea nitrogen, creatinine, uric acid), and with the immune response (neutrophils/lymphocytes) and activation (kynurenine/tryptophan). 43 significant NDM/LDM metabolites (including urea) were co-associated with at least 1 marker of renal function; 23 of these metabolites have been previously identified as uremic solutes. The neutrophil/lymphocyte ratio was significantly associated with NDM/LDM (?±SE: -0.3±0.1, p=0.01, q=0.04). 35 significant NDM/LDM metabolites were co-associated with immune activation. Carbamylation (defined as homocitrulline/lysine) was identified as a pathway that may link renal function and immune activation with muscle composition, as 29 significant NDM/LDM metabolites were co-associated with homocitrulline/lysine, with at least 2 markers of renal function, and with kynurenine/tryptophan. When considering that elevated urea and uremic metabolites have been linked with an increased systemic microbial burden, that antimicrobial defense can be reduced in the presence of carbamylation, and that adipocytes can promote host defense, we propose the novel hypothesis that the age-related increase in adipogenesis within muscle may be a compensatory antimicrobial response to protect against an elevated microbial burden.

Project description:Exercise has multi-systemic benefits and attenuates the physiological impairments associated with aging. Emerging evidence suggests that circulating exosomes mediate some of the beneficial effects of exercise via the transfer of microRNAs between tissues. However, the impact of regular exercise and acute exercise on circulating exosomal microRNAs (exomiRs) in older populations remains unknown. In the present study, we analyzed circulating exomiR expression in endurance-trained elderly men and age-matched sedentary males at baseline (Pre), immediately after a forty minute bout of aerobic exercise on a cycle ergometer (Post), and three hours after this acute exercise (3hPost). Plasma exosomes were isolated, characterized, and exomiR levels were determined by sequencing. The effect of regular exercise on circulating exomiRs was assessed using paired t-tests of baseline expression levels in the trained and sedentary groups. The effect of acute exercise was determined by comparing baseline and post-training expression levels in each group. Regular exercise resulted in significantly increased baseline expression of three exomiRs (miR-486-5p, miR-215-5p, miR-941) and decreased expression of one exomiR (miR-151b). Acute exercise altered circulating exomiR expression in both groups. However, exomiRs regulated by acute exercise in the trained group (7 miRNAs at Post and 8 at 3hPost) were distinct from those in the sedentary group (9 at Post and 4 at 3hPost). Pathway analysis prediction and reported target validation experiments revealed that the majority of exercise-regulated exomiRs are targeting genes that are related to IGF-1 signaling, a pathway involved in exercise-induced muscle and cardiac hypertrophy. The immediately post-acute exercise exomiR signature in the trained group correlates with activation of IGF-1 signaling, whereas in the sedentary group it is associated with inhibition of IGF-1 signaling. These results suggest that training status may counteract age-related anabolic resistance by modulating circulating exomiR profiles both at baseline and in response to acute exercise.

Dataset Information

Metabolites Associated With Circulating Interleukin-6 in Older Adults.

Background

Methods

Results

Conclusions

Publications

Metabolites Associated With Circulating Interleukin-6 in Older Adults.

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