Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 15 No.
1 • January-February 2012
Chronic Low Grade Inflammation in Aged Humans Associated with Reduced Tryptophan and Depressive Symptoms
A new paper explored the hypothesis that chronic low grade inflammation as is found in aged individuals might play a role in the neuropsychiatric symptoms (such as lassitude, reduced motivation, anorexia, and pessimism) commonly occurring in the aged. The researchers first note that inflammation affects the activity of two enzymatic pathways involved in the regulation of tryptophan (indoleamine-2,3-dioxygenase, IDO) and phenylalanine and tyrosine (guanosine-triphosphate-cyclohydrolase-1, GTP-CH1), suggesting a possible mechanism for the link between inflammation and neuropsychiatric symptoms. Interestingly, tryptophan metabolites generated by the kynurenine pathway (which includes IDO) are thought to play an important role in neurodegenerative disorders, such as Alzheimer’s and Huntington’s diseases and possibly in the development of senile cataracts.
“Indoleamine-2,3-dioxygenase can be induced by inflammatory cytokines, including most notably interferons (IFN) in a variety of immune cells such as monocyte-derived macrophages and microglia. When activated, IDO catalyzes the rate-limiting step of tryptophan conversion into kynurenine ... In vivo, the ratio of kynurenine/tryptophan (Kyn/Trp) reflects tryptophan breakdown and is considered to represent one estimate of IDO activity.”
In their study, 284 subjects were included, with the mean age of 79.9 years (SD=4.5 years). “The older participants were, the lower were tryptophan levels and the higher were IL-6, kynurenine, and neopterin [produced by activated GTP-CH1] concentrations and the ratio of Kyn/Trp. In addition, there was a trend [not quite significant] for a relationship between age and tyrosine concentrations, with increased age corresponding to decreased tyrosine levels.”
“Neuropsychiatric scores were evaluated by the MADRS, MFI, and NRS scales. Higher MADRS scores of lassitude were associated with lower tryptophan and phenylalanine concentrations. Moreover, there was a trend for a relationship between reduced tryptophan concentrations and increased MADRS scores of pessimistic thoughts.” “Reduced phenylalanine turnover has been documented in various medical conditions characterized by chronic inflammation.” “Altogether, these findings indicate that age-related chronic inflammation is associated with potent alterations in enzymatic pathways that are strongly involved in the biosynthesis of neurotransmitters, incliding serotonin, dopamine, epinephrine, and norepinephrine.”
The researchers note that nutritional interventions such as tryptophan supplements might not work if the added tryptophan is overcome by breakdown of tryptophan by IDO induced by chronic inflammation or if adequate vitamin B6 (a cofactor for tryptophan production) were not present. (Note: Our serenity line of tryptophan and 5-hydroxytryptophan supplements all include vitamin B6.) However, there are substances that reduce in vitro tryptophan degradation by IDO. For example, resveratrol, vitamins C and E, and aspirin have been shown to reduce in vitro tryptophan degradation and neopterin production. Another paper reports that curcumin suppresses the induction of IDO in interferon-gamma-stimulated mouse dendritic cells. EGCG (epigallocatechin gallate, a major bioactive constituent of green tea) is also reported to suppress IDO. However, it is not clear from the sparse data available for in vitro inhibition of IDO by natural products such as those mentioned here what in vivo dose would be required. We will be closely following new developments in this line of research.
A paper reporting on the effects of aspirin on tryptophan degradation found that 1–5 mM aspirin slightly increased tryptophan concentrations in resting human peripheral blood mononuclear cells (PBMCs) but that preincubation of stimulated PBMCs with 5 mM aspirin significantly decreased tryptophan degradation. The authors report that “[i]n our investigation, salicylic acid at similar concentrations to aspirin suppressed tryptophan degradation and neopterin production in stimulated PBMC.”
A paper on inhibition of IDO by niacinamide indicated that, in human subjects with HIV infection, IDO induced by interferon gamma was suppressed (resulting in an increase of tryptophan levels by 40%) by 3 grams of niacinamide a day. Niacin was reported in the same paper (though no study was cited) to also inhibit tryptophan degradation by IDO. Unfortunately, the flushing side effect makes niacin intolerable to many people, but if you don’t mind it, you can take up to 800 mg of niacin a day without having liver tests. That may help prevent degradation of tryptophan. Niacinamide is more toxic than niacin and, consequently, we do not recommend using it, certainly not at the 3 gram dose a day unless under close medical supervision. Interestingly, increased degradation of tryptophan has been reported in blood of patients with rheumatoid athritis. As the authors explain in their introduction: “The kynurenine-tryptophan ratio (kyn/trp) allows an estimate for IDO activity and was found to be increased in states of persistent immune activation, i.e., infectious and malignant diseases.” “The data [in this study] point to a role of immune activation and Th1 [proinflammatory]-type cytokine INF-gamma to induce elevated tryptophan degradation in patients with RA [rheumatoid arthritis].”
1. Capuron et al. Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine metabolism: role in neuropsychiatric symptoms. Biol Psychiatry 70:175-82 (2011).
1a. Zwilling et al. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell 145:863-74 (2011).
1a2. Pereira et al. Indoleamine 2,3-dioxygenase inhibitors from the northeastern pacific marine hydroid Garveia annulata. J Nat Prod 69:1496-9 (2006).
1b. Wirleitner et al. Resveratrol suppresses interferon-gamma-induced biochemical pathways in human peripheral blood mononuclear cells in vitro. Immunol Lett 100:159-63 (2005).
1c. Young-II Jeong et al. Curcumin suppresses the induction of indoleamine-2,3-dioxygenase by blocking the Janus-activated Kinase-protein kinase Cdelta-STAT1 signaling pathway in interferon-gamma-stimulated murine dendritic cells. J Biol Chem 284(6):3700-8 (2009). “Recent in vivo studies suggest that IDO-expressing DCs [dendritic cells] isolated from tumor-draining lymph nodes contribute to the progression of tumors by creating local immunosuppression.”
1d. Cheng et al. Indoleamine 2,3-dioxygenase, an immunomodulatory protein, is suppressed by (-)-epigallocatechin- 3-gallate via blocking of gamma-interferon-induced JAK-PKC-delta- STAT1 signaling in human oral cancer cells. J Agric Food Chem 58:887-94 (2010).
1e. Winkler et al. Vitamins C and E suppress mitogen-stimulated peripheral blood mononuclear cells in vitro. Int Arch Allergy Immunol 142:127-32 (2007).
1f. Murray. Tryptophan depletion and HIV infection: a metabolic link to pathogenesis. Lancet Infect Dis 3:644-52 (2003).
2. Schroecksnadel et al. Aspirin down-regulates tryptophan degradation in stimulated human peripheral blood mononuclear cells in vitro. Clin Exp Immunol 140:41-5 (2005).
3. Schroecksnadel et al. Increased degradation of tryptophan in blood of patients with rheumatoid arthritis. J Rheumatol 30(9):1935-9 (2003).