Metabolic syndrome, age-associated neuroendocrine disorders, and dysregulation of tryptophan-kynurenine metabolism

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 Icynurenines 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 PIG 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.