Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target

Abstract

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.

Keywords: aging; indoleamine 2,3 dioxygenases (IDO); inflammaging; inflammation; kynurenine; tryptophan; tryptophan 2,3-dioxygenase (TDO).

Figure 1

Mechanisms involved the regulation of inflammation by Trp metabolism. Inflammation activates Trp metabolism and causes systemic and intra- and extra-cellular changes in the Kyn/Trp ratio that suppress the inflammatory response (A). The molecular steps involved in the immunomodulatory effect of activation of Trp metabolism (B): An inflammatory stimulus activates IDO (and in specific instances TDO) in immune and non-immune cells causing reduced Trp systemic and local Trp levels and increased intra- and extracellular Kyn content (1); inflammation induces increased expression of AhR (2) that is activated by its ligand Kyn and results in the secretion of anti-inflammatory cytokines such as IL-10 (3); AhR ligand-activation causes phosphorylation of IDO and results in sustained IDO activity and the secretion of TGF-β, which is involved in a feedback loop by inducing IDO phosphorylation (4); inflammatory cytokines such as TGF-β and IL-10 induce the amino acid transporter SLC7A5 on the plasma membrane of naïve T-cells causing transport of Kyn into the T cell (5); activation of GCN2 by Trp depletion and AhR ligand-activation by Kyn cause the differentiation of naïve T cells toward regulatory T cells (6). Solid arrows indicate regulatory (transcriptional or translational) and enzymatic effects, dashed arrows indicate active or passive cross-cellular and cross-compartmental transport of Trp and Kyn. Trp, Tryptophan; Kyn, Kynurenine, IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase; AhR, aryl hydrocarbon receptor; TGF-β, tissue growth factor beta; IL-10, interleukin 10; SLC7A5, solute carrier family 7 member 5; GCN2, general control non-derepressable 2 stress kinase.

Figure 2

Implications of inflammaging-dependent shunt of Trp metabolism. Age-related decline of tissue homeostasis causes a physiological low-grade chronic inflammatory phenotype known as inflammaging. We hypothesize that Trp is metabolized toward the Kyn pathway in order to control age-related inflammation. Consequent disturbances of Trp and Kyn metabolites could be involved in age-related diseases and reduced lifespan.