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Insulin resistance (IR) underlines aging and aging-associated medical (diabetes, obesity, dyslipidemia, hypertension) and psychiatric (depression, cognitive decline) disorders (AAMPD). Molecular mechanisms of IR in genetically or metabolically predisposed individuals remain uncertain. Current review of literature and our data presents the evidences that dysregulation of tryptophan (TRP) – kynurenine (KYN) and KYN – nicotinamide adenine dinucleotide (NAD) metabolic pathways is one of the mechanisms of IR. First and rate-limiting step of TRP – KYN pathway is regulated by enzymes inducible by pro-inflammatory factors and/or stress hormones. The key enzymes of KYN – NAD pathway require pyridoxal-5-phosphate (P5P), an active form of vitamin B6, as a co-factor. Deficiency of P5P diverts KYN – NAD metabolism from production of NAD to the excessive formation of xanthurenic acid (XA). Human and experimental studies suggested that XA and some other KYN metabolites might impair production, release and biological activity of insulin. We propose that one of the mechanisms of IR is inflammation- and/or stress-induced up-regulation of TRP – KYN metabolism in combination with P5P deficiency-induced diversion of KYN – NAD metabolism towards formation of XA and other KYN derivatives affecting insulin activity. Monitoring of KYN/P5P status and formation of XA might help to identify subjects-at-risk for IR. Pharmacological regulation of the TRP – KYN and KYN – NAD pathways and maintaining of adequate vitamin B6 status might contribute to prevention and treatment of IR in conditions associated with inflammation/stress–induced excessive production of KYN and deficiency of vitamin B6, e.g., diabetes type 2, obesity, cardiovascular diseases, aging, menopause, pregnancy, and hepatitis C virus infection.

The neuroendocrine theory of aging identified a cluster of conditions (hypertension, obesity, dyslipidemia, diabetes type 2, menopause, late onset depression, vascular cognitive impairment, impairment of immune defense, and some forms of cancer, e.g., breast and prostate) as age-associated neuroendocrine disorders (AAND). Obesity, dyslipidemia, hypertension, and type 2 diabetes were later described as metabolic syndromes (MetS). Chronic inflammation is currently considered as a common feature of MetS/AAND. One of the mechanisms by which chronic inflammation might trigger and/or maintain the development of MetS/AAND is transcriptional induction of indoleamine 2,3-dioxygenase (IDO), rate-limiting enzyme of tryptophan (TRY)-kynurenine (KYN) pathway, by pro-inflammatory cytokines (PIC). Activation of IDO shifts TRY metabolism from serotonin synthesis to formation of "kynurenines." Diminished serotonin production is associated with mental depression while increased formation of kynurenines might contribute to development of MetS/AAND via their apoptotic, neurotoxic, and pro-oxidative effects, and upregulation of inducible nitric oxide synthase, phospholipase A2, arachidonic acid, prostaglandin, 5-lipoxygenase, and leukotriene cascade. The combined presence of high producers of alleles of polymorphic PIC genes (e.g., interferon-gamma and tumor necrosis factor alpha) might account for the genetic predisposition to high levels of PIC production, leading to "superinduction" of IDO. The other rate-limiting enzyme of the TRY-KYN pathway, TRY 2,3-dioxygenase, is activated by substrate (TRY) and cortisol. Therefore, KYN-TRY metabolism might be the meeting point for gene-environment interaction and a new target for prevention and treatment of MetS/AAND.

Mitochondrial permeability transition pores represent a multiprotein complex that includes components of both inner and outer membrane. The pores regulate transport of ions and peptides in and out of mitochondria, and their regulation is associated with a general mechanism for maintaining Ca(2+) homeostasis in the cell and apoptosis. Various pathologic factors may induce a pathologic activation of the permeability transition and an irreversible opening of mitochondria pores. This event is a major step in the development of neurotoxicity and neurodegeneration. This paper explores the effect of MPP(+) and beta-amyloid fragment 25-35, neurotoxins that are known to generate Parkinson's-like syndrome and Alzheimer's disease, on the regulation of the mitochondrial pores. Both neurotoxins induce opening of mitochondrial pores, which is prevented by cyclosporin A, a specific inhibitor of the permeability transition. The effect of MPP(+) and beta-amyloid may be also prevented by an endogenous precursor of melatonin, N-acetylserotonin, by an anti-Alzheimer's medication tacrine, and by dimebon, which is in development as an agent for the therapy of Alzheimer's disease and other types of dementia. The paper illustrates that the effect on mitochondrial pores is an important aspect of the mechanism of neurotoxicity. Substances that may prevent opening of mitochondrial pores induced by neurotoxins may preserve the mitochondrial function and, thus, may have potential as neuroprotective agents.

This review of literature and our data suggests that up-regulated production of interferon-gamma (IFNG) in periphery and brain triggers a merger of tryptophan (TRY)–kynurenine (KYN) and guanine–tetrahydrobiopterin (BH4) metabolic pathways into inflammation cascade involved in aging and aging-associated medical and psychiatric disorders (AAMPD) (metabolic syndrome, depression, vascular cognitive impairment). IFNG-inducible KYN/pteridines inflammation cascade is characterized by up-regulation of nitric oxide synthase (NOS) activity (induced by KYN) and decreased formation of NOS cofactor, BH4, that results in uncoupling of NOS that shifting arginine from NO to superoxide anion production. Superoxide anion and free radicals among KYN derivatives trigger phospholipase A2-arachidonic acid cascade associated with AAMPD. IFNG-induced up-regulation of indoleamine 2,3-dioxygenase (IDO), rate-limiting enzyme of TRY–KYN pathway, decreases TRY conversion into serotonin (substrate of antidepressant effect) and increases production of KYN associated with diabetes [xanthurenic acid (XA)], anxiety (KYN), psychoses and cognitive impairment (kynurenic acid). IFNG-inducible KYN/pteridines inflammation cascade is impacted by IFNG (+874) T/A genotypes, encoding cytokine production. In addition to literature data on KYN/TRY ratio (IDO activity index), we observe neopterin levels (index of activity of rate-limiting enzyme of guanine–BH4 pathway) to be higher in carriers of high (T) than of low (A) producers alleles; and to correlate with AAMPD markers (e.g., insulin resistance, body mass index, mortality risk), and with IFN-alpha-induced depression in hepatitis C patients. IFNG-inducible cascade is influenced by environmental factors (e.g., vitamin B6 deficiency increases XA formation) and by pharmacological agents; and might offer new approaches for anti-aging and anti-AAMPD interventions.

In the late 60th - early 70th of the last century Prof. IP Lapin (June 26, 1930 – August 23, 2012) suggested that “intensification of central serotoninergic processes is a determinant of the thymoleptic (mood elevating) component” while “activation of noradrenergic processes is responsible for psychoenergetic and motor-stimulating component of the clinical antidepressant effect”. He suggested that in depression cortisol-inducible activation of liver enzyme, tryptophan 2,3-dioxygenase (TDO), shunted “metabolism of tryptophan away from serotonin production towards kynurenine production” leading to serotonin deficiency. He was the first to suggest and discover that kynurenine and its metabolites affect brain functions, and propose the role of neurokynurenines in pathogenesis of depression and action mechanisms of antidepressant effect. Further major developments of serotonin-kynurenine hypothesis include the discovery of antidepressant and cognition-enhancing effects of post-serotonin metabolite, N-acetylserotonin, an agonist to tyrosine kinase B(TrkB) receptors of brain derived neurotrophic factor. The discovery of indoleamine 2,3–dioxygenase (IDO), another rate-limiting enzyme of TRY – KYN metabolism, located in brain and inducible by pro-inflammatory cytokines, suggested the link between depression and aging/aging-associated medical (e.g., insulin resistance, obesity, cardiovascular), psychiatric (e.g., vascular cognitive impairment) and other disorders associated with chronic inflammation (e.g., hepatitis virus C, psoriasis) disorders.

About 350 million people worldwide have type 2 diabetes (T2D). The major risk factor of T2D is impaired glucose tolerance (pre-diabetes) with 10% of pre-diabetes subjects develop T2D every year. Understanding of mechanisms of development of T2D from pre-diabetes is important for prevention and treatment of T2D. Chronic stress and chronic low grade inflammation are prominent risk factors for T2D development in pre-diabetic subjects. However, molecular mechanisms mediating effect of stress and inflammation on development of T2D from pre-diabetes remain unknown. One of such mechanisms might involve kynurenine (KYN) pathway (KP) of tryptophan (TRP) metabolism. We suggested that chronic stress- or chronic low grade inflammation-induced upregulation of formation of upstream KTP metabolites, KYN and 3-hydroxyKYN, combined with chronic stress or chronic low grade inflammation-induced deficiency of pyridoxal 5'-phosphate, a cofactor of downstream enzymes of KTP, triggers overproduction of diabetogenic downstream KYN metabolites, kynurenic acid (KYNA) and 3-hydroxyKYNA (also known as xanthurenic acid (XA)). As the initial assessment of our working hypothesis, we evaluated plasma levels of up- and down-stream KP metabolites in the same samples of T2D patients. KYN, XA and KYNA levels in plasma samples of T2D patients were higher than in samples of non-diabetic subjects. Our results provide further support of “kynurenine hypothesis of insulin resistance and its progression to T2D” that suggested that overproduction of diabetogenic KP metabolites, induced by chronic stress- or chronic low grade inflammation, is one of the mechanisms promoting development of T2D from pre-diabetes. Downstream metabolites of KP might serve as biomarkers of T2D and targets for clinical intervention.

This review provides information on the most recent findings concerning presence, origin, and role of kynurenic acid (KYNA), a tryptophan metabolite, in the digestive system. KYNA is an antagonist of both the ionotropic glutamate receptors and the alpha7 nicotinic acetylcholine receptor, as well as an agonist of G-protein coupled GPR35 receptor. Since the GPR35 receptor is mainly present in the gastrointestinal tract, researchers have concentrated on the digestive system in recent years. They have found that KYNA content increases gradually and significantly along the gastrointestinal tract. Interestingly, the concentration of KYNA in the lumen is much higher than in the wall of intestine. It has been documented that KYNA may have a positive influence on the number of pathologies in the gastrointestinal tract, in particular ulcers, colon obstruction, or colitis. Future studies might determine whether it is advisable to supplement KYNA to a human organism.