Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 16 No. 3 • March 2013


Delayed Aging and Aging-Associated Decline of Protein Function by Inhibiting Tryptophan Degradation

A very interesting new study reports that preventing the enzymatic degradation of tryptophan has significant anti-aging effects in the nematode Caenorhabditis elegans. The study specifically identifies “the tryptophan-converting enzyme tryptophan 2,3-dioxygenase (TDO-2) as a metabolic regulator of age-related protein toxicity and lifespan in C. elegans.”1

The researchers found that depletion of TDO-2 suppressed toxicity of aggregation-prone proteins, including alpha-synuclein, amyloid-beta and polyglutamine proteins, associated with diseases such as Parkinson’s, Alzheimer’s, and Huntington’s, respectively. Depletion of TDO-2, the first enzyme in the kynurenine pathway of tryptophan degradation, increased the levels of tryptophan (by decreasing its degradation), but the researchers also found that feeding the worms with extra ­L-tryptophan also suppressed the toxicity of aggregation-prone proteins. (Emphasis added.) Moreover, depletion of TDO-2 extended lifespan in C. elegans. Humans have evolutionarily conserved orthologs of TDO-2 (TDO and indoleamine 2,3-dioxygenase). Hence, the authors conclude, “intervening with tryptophan metabolism may offer avenues to reducing proteotoxicity in aging and age-related diseases.”1

The researchers also note that as TDO-2 naturally increases during aging, this may contribute to the age-dependent decline in protein homeostasis and, thus, inhibiting TDO (and possibly indoleamine 2,3-dioxygenase) may delay this process.

Other Natural Products Inhibit Indoleamine 2,3-Dioxygenase

Indoleamine 2,3-dioxygenase has been shown to have important effects on the immune system. “By locally degrading tryptophan, IDO inhibits the proliferation of T lymphocytes and induces T cell apoptosis, leading to suppression T cell response.”2 In a recent study, EGCG (the major catechin constituent of green tea) was shown to significantly inhibit the expression of IDO (and hence preventing immune suppression of T cells resulting from the degradation of tryptophan) in oral cancer cell lines.2

In another study,3 curcumin was reported to reverse IDO-mediated suppression of T-cell responses in bone marrow-derived dendritic cells stimulated by interferon gamma. The authors suggest that “down regulation of IDO in DCs is an important immunomodulatory property of curcumin that may be exploited therapeutically in the control of cancers.”

A study on the effects of resveratrol on IDO4 reports that in a cell culture study, resveratrol (10–100 uM) diminished tryptophan degradation by IDO.

Reduced Neurogenesis by TDO-2 Conversion of Tryptophan into Kynurenine, Catalyzed by Tryptophan-2,3-dioxygenase, is Stimulated By Cytokine-Induced Depression

Another result of degradation of tryptophan by tryptophan-2,3-dioxygenase (TDO-2) is decreased neuro­genesis.5 In a 2012 paper,5 researchers report that “[t]he first step [in the conversion of tryptophan to kynurenine] is catalyzed by the enzyme tryptophan-2,3-dioxygenase and, especially in response to inflammation, also by indoleamine-2,3-dioxygenase (IDO). This pathway is clearly activated during cytokine-induced depression. For example, administration of LPS [lipopolysaccharide, a component of bacterial cell wall, which stimulates the immune system] in rodents activates IDO and induces depression-like symptoms, which in turn can be prevented by an IDO antagonist.” Importantly, the researchers go on to explain that “[f]ollowing IDO activation, both the reduced peripheral availability of tryptophan (putatively leading to reduced serotonin synthesis in the brain) and the relative balance between QUIN [quinolinic acid] and KYNA [kynurenic acid] [both products of TDO and/or IDO], have been proposed to be of significance in depression and neurodegeneration. Indeed, TDO-/- [TDO knockout] mice show increased neurogenesis.” Accordingly, the researchers chose to test the hypothesis that the kynurenine pathway is involved in the IL-1beta (a proinflammatory cytokine)-induced reduction of neurogenesis.

The researchers report finding that differentiated human hippocampal progenitor cells constitutively express both IDO and TDO, the enzymes that degrade tryptophan into KYN (kynurenine). In culture of the cells, it was found that tryptophan levels decreased by 19% and kynurenine levels increased by 20%, leading to an overall 53 ± 13% (p<0.05) increase in the ratio of kynurenine/tryptophan. In other words, the IL-1beta increased the levels of a functional IDO enzyme.

The authors conclude that “our results show for the first time that IL-1beta reduces human hippocampal neuro­genesis …” “We also show that, upon activation of IDO, treatment with IL-1beta results in a decrease of tryptophan together with an increase in kynurenine levels.”5

Another new paper6 also reports, in a mouse model of neuroinflammation-induced depression, that the inhibition of indoleamine 2,3-dioxygenase by its competitive inhibitor 1-methyl-tryptophan, prevented the development of depressive-like behavior. This is consistent with current thinking that the activation of IDO by proinflammatory cytokines is a link between IDO and neurodegenerative diseases such as Alzheimer’s disease and depression.6

References

  1. van der Goot et al. Delayed aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation. Proc Nat Acad Sci USA. 109(37):14912-7 (2012).
  2. 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. Jnbsp;Agric Food Chem. 58:887-94 (2010).
  3. Jeong et al. Curcumin suppresses the induction of indoleamine 2,3-dioxygenase by blocking the Janus-activated Kinase-protein kinasew Cdelta-STAT1 signaling pathway in interferon-gamma-stimulated murine dendritic cells. Jnbsp;Biol Chem. 284(6):3700-8 (2009).
  4. Wirleitner et al. Resveratrol suppresses interferon-gamma-induced biochemical pathways in human peripheral blood mononuclear cells in vitro. Immunol Lett. 100:159-63 (2005).
  5. Zunszain et al. Interleukin-1beta: A new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. Neuropsychopharmacol. 37:939-49 (2012).
  6. Dobos et al. The role of indoleamine 2,3-dioxygenase in a mouse model of neuroinflammation-induced depression. J Alzheimers Dis. 28:905-15 (2012).

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