Immunological alterations in frail older adults: A cross sectional study

Valdiglesias, Vanessa; Marcos-Pérez, Diego; Lorenzi, Maria; Onder, Graziano; Gostner, Johanna M.; Strasser, Barbara; Fuchs, Dietmar; Bonassi, Stefano

doi:10.1016/j.exger.2018.09.010

Cited by 45 publications

(36 citation statements)

References 48 publications

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“…In humans, increased IDO1 activity and higher Kyn plasma concentrations have been positively correlated to older age (31), although gender and disease state may also play roles. Increased IDO activity is linked to higher mortality in humans (42), and an increased Kyn/Trp ratio is associated with human frailty (43). We found that in women (ages 18‐75), increased age positively correlated with obesity and rising Kyn plasma levels (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Kynurenine‐Induced Aryl Hydrocarbon Receptor Signaling in Mice Causes Body Mass Gain, Liver Steatosis, and Hyperglycemia

Rojas

Moyer

Ringelberg

et al. 2021

Obesity

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Objective: The aryl hydrocarbon receptor (AHR) plays a key role in obesity. In vitro studies revealed that the tryptophan metabolite kynurenine (Kyn) activates AHR signaling in cultured hepatocytes. The objective of this study was to determine whether Kyn activated the AHR in mice to induce obesity. Methods: Mice were fed a low-fat diet and the same diet supplemented with Kyn. Body mass, liver status, and the expression of identified relevant genes were determined. Results: Kyn caused mice to gain significant body mass, develop fatty liver and hyperglycemia, and increase expression levels of cytochrome P450 1B1 and stearoyl-CoA desaturase 1. The hyperglycemia was accompanied with decreased insulin levels, which may have been due to the repression of genes involved in insulin secretion. Kyn plasma concentrations and BMI were measured in female patients, and a significant association was observed between Kyn and age in patients with obesity but not in patients who were lean. Conclusions: Results show that (1) Kyn or a metabolite thereof is a ligand responsible for inducing AHR-based obesity, fatty liver, and hyperglycemia in mice; (2) plasma Kyn levels increase with age in women with obesity but not in lean women; and (3) an activated AHR is necessary but not sufficient to attain obesity, a status that also requires fat in the diet.

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Section: Discussionmentioning

confidence: 99%

Kynurenine‐Induced Aryl Hydrocarbon Receptor Signaling in Mice Causes Body Mass Gain, Liver Steatosis, and Hyperglycemia

Rojas

Moyer

Ringelberg

et al. 2021

Obesity

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“…We addressed this knowledge gap by examining the cellular and molecular mechanisms underlying the age-associated accumulation of reactive oxygen species. KYN is a circulating tryptophan metabolite that increases with age and is correlated with frailty [11] and increased mortality in older adults [10]. Elevated circulating levels of KYN are also found to be associated with osteoporosis and Alzheimer's disease [7, 25, 26].…”

Section: Discussionmentioning

confidence: 99%

“…IDO is induced by several inflammatory cytokines including IL-6, IL-1 β , and interferon-gamma (IFN γ ) [9]. An increase in IDO activity has been linked to an increased mortality rate in humans [10], and frailty is associated with a marked increase in the KYN/TRP ratio [11].…”

Section: Introductionmentioning

confidence: 99%

Kynurenine, a Tryptophan Metabolite That Increases with Age, Induces Muscle Atrophy and Lipid Peroxidation

Kaiser

Pandya

et al. 2019

Oxidative Medicine and Cellular Longevity

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The cellular and molecular mechanisms underlying loss of muscle mass with age (sarcopenia) are not well-understood; however, heterochronic parabiosis experiments show that circulating factors are likely to play a role. Kynurenine (KYN) is a circulating tryptophan metabolite that is known to increase with age and is a ligand of the aryl hydrocarbon receptor (Ahr). Here, we tested the hypothesis that KYN activation of Ahr plays a role in muscle loss with aging. Results indicate that KYN treatment of mouse and human myoblasts increased levels of reactive oxygen species (ROS) 2-fold and KYN treatment in vivo reduced muscle size and strength and increased muscle lipid peroxidation in young mice. PCR array data indicate that muscle fiber size reduction with KYN treatment reduces protein synthesis markers whereas ubiquitin ligase gene expression is not significantly increased. KYN is generated by the enzyme indoleamine 2,3-dioxygenase (IDO), and aged mice treated with the IDO inhibitor 1-methyl-D-tryptophan showed an increase in muscle fiber size and muscle strength. Small-molecule inhibition of Ahr in vitro, and Ahr knockout in vivo, did not prevent KYN-induced increases in ROS, suggesting that KYN can directly increase ROS independent of Ahr activation. Protein analysis identified very long-chain acyl-CoA dehydrogenase as a factor activated by KYN that may increase ROS and lipid peroxidation. Our data suggest that IDO inhibition may represent a novel therapeutic approach for the prevention of sarcopenia and possibly other age-associated conditions associated with KYN accumulation such as bone loss and neurodegeneration.

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“…This is the case for the Kyn/Trp ratio. For example, an increased Kyn/Trp ratio was found to be associated with increased frailty (63), reduced cognitive performance (64), increased risk of cardiovascular disease (65, 66) and mortality (56, 66) in aged individuals. Other Kyn metabolites, including the 3-hydroxyanthranilic acid/anthranilic acid ratio and kynurenic acid, have also been associated with inflammation and poor outcome in the context of (age-related) diseases of the brain (67, 68).…”

Section: Tryptophan Metabolism As a Biomarker And Therapeutic Target mentioning

confidence: 99%

Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target

et al. 2019

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Inflammation aims to restore tissue homeostasis after injury or infection. Age-related decline of tissue homeostasis causes a physiological low-grade chronic inflammatory phenotype known as inflammaging that is involved in many age-related diseases. Activation of tryptophan (Trp) metabolism along the kynurenine (Kyn) pathway prevents hyperinflammation and induces long-term immune tolerance. Systemic Trp and Kyn levels change upon aging and in age-related diseases. Moreover, modulation of Trp metabolism can either aggravate or prevent inflammaging-related diseases. In this review, we discuss how age-related Kyn/Trp activation is necessary to control inflammaging and alters the functioning of other metabolic faiths of Trp including Kyn metabolites, microbiota-derived indoles and nicotinamide adenine dinucleotide (NAD+). We explore the potential of the Kyn/Trp ratio as a biomarker of inflammaging and discuss how intervening in Trp metabolism might extend health- and lifespan.

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Immunological alterations in frail older adults: A cross sectional study

Cited by 45 publications

References 48 publications

Kynurenine‐Induced Aryl Hydrocarbon Receptor Signaling in Mice Causes Body Mass Gain, Liver Steatosis, and Hyperglycemia

Kynurenine‐Induced Aryl Hydrocarbon Receptor Signaling in Mice Causes Body Mass Gain, Liver Steatosis, and Hyperglycemia

Kynurenine, a Tryptophan Metabolite That Increases with Age, Induces Muscle Atrophy and Lipid Peroxidation

Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target

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