Interferon-gamma - Inducible Inflammation: Contribution to Aging and Aging-Associated Psychiatric Disorders

Aging is associated with the chronic, low grade, Th-1 type inflammation. The key Th-1 type, pro-inflammatory cytokine, interferon-gamma (IFNG), transcriptionally induces the rate-limiting enzyme of tryptophan (TRY) - kynurenine (KYN) pathway, indoleamine 2,3- dioxygenase (IDO). Activation of IDO shunts TRY metabolism from production of serotonin (substrate of antidepressant effect) and its derivatives: N-acetylserotonin (an agonist to the receptors of brain derived neurotropic factor), and melatonin (regulator of sleep and other circadian rhythms), towards production of KYN and its derivatives (anxiogenic, neurotoxic and pro-oxidant factors). Some of kynurenines up-regulate nitric oxide synthase (NOS). Concurrently with activation of IDO, IFNG induces guanosine triphosphate cyclohydrolase I (GTPCH), the rate limiting enzyme of GTP conversion into BH2 (and increases formation of a stable derivative of BH2, neopterin, at the expense of production of BH4, the mandatory co-factor of NOS). Combination of increased NOS activity (by kynurenines) with decreased formation of BH4 leads to the uncoupling of NOS with consequent shift of arginine metabolism from biosynthesis of NO to formation of superoxide anion and other free radicals, and exacerbation of depression, anxiety and cognitive impairment caused by kynurenines. Polymorphism of IFNG (+874) T/A gene, that encodes production of IFNG protein, impacts the IDO and GTPCH activity that might be assessed in humans by KYN/TRY ratio and neopterin concentrations in biological fluids (e.g., blood, urine and spinal fluid). The hypothesis of IFNG inducible IDO/GTPCH inflammation cascade helps to understand the increased association between aging, inflammation and aging-associated psychiatric and medical (insulin resistance, obesity) disorders. Evaluation of markers of IFNG-inducible inflammation cascade might be used to assess the severity of corresponding behavioral and cognitive changes and the efficacy of pharmacological interventions (e.g., IDO inhibitors).