Kynurenine pathway, NAD+ synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan

Castro-Portuguez, Raúl; Sutphin, George L.

doi:10.1016/j.exger.2020.110841

Cited by 183 publications

(118 citation statements)

References 146 publications

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“…Interestingly, thanks to the experimental setup implemented in this study, this alteration of the kynurenine pathway was shown to be specific to male mussels. In humans, the kynurenine pathway has received increasing attention because of its connection to the immune system and the de novo synthesis of nicotinamide adenine dinucleotide (NAD+), which plays a critical role in many enzymatic redox reactions and in mitochondrial energy production [ 44 ]. A potential toxicity of the WWTP effluent on the immune system and energy metabolism on male mussels was also demonstrated in our previous study [ 28 ].…”

Section: Resultsmentioning

confidence: 99%

Multifactorial Analysis of Environmental Metabolomic Data in Ecotoxicology: Wild Marine Mussel Exposed to WWTP Effluent as a Case Study

et al. 2020

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Environmental metabolomics is a powerful approach to investigate the response of organisms to contaminant exposure at a molecular scale. However, metabolomic responses to realistic environmental conditions can be hindered by factors intrinsic to the environment and the organism. Hence, a well-designed experimental exposure associated with adequate statistical analysis could be helpful to better characterize and relate the observed variability to its different origins. In the current study, we applied a multifactorial experiment combined to Analysis of variance Multiblock Orthogonal Partial Least Squares (AMOPLS), to assess the metabolic response of wild marine mussels, Mytilus galloprovincialis, exposed to a wastewater treatment plant effluent, considering gender as an experimental factor. First, the total observed variability was decomposed to highlight the contribution of each effect related to the experimental factors. Both the exposure and the interaction gender × exposure had a statistically significant impact on the observed metabolic alteration. Then, these metabolic patterns were further characterized by analyzing the individual variable contributions to each effect. A main change in glycerophospholipid levels was highlighted in both males and females as a common response, possibly caused by oxidative stress, which could lead to reproductive disorders, whereas metabolic alterations in some polar lipids and kynurenine pathway were rather gender-specific. This may indicate a disturbance in the energy metabolism and immune system only in males. Finally, AMOPLS is a useful tool facilitating the interpretation of complex metabolomic data and is expected to have a broad application in the field of ecotoxicology.

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Section: Resultsmentioning

confidence: 99%

Multifactorial Analysis of Environmental Metabolomic Data in Ecotoxicology: Wild Marine Mussel Exposed to WWTP Effluent as a Case Study

et al. 2020

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“…It is also possible that it might be more practical to inhibit the kynurenine pathway and selectively add back metabolites that are of benefit; for example, Castro-Portugez and Suthphin [84] have suggested inhibition of the kynurenine pathway with selective replacement of NAD+. NAD+ is important in mitochondrial bioenergetics and supplementation has been associated with increased longevity [88]. Inhibition of the first step in this pathway by inhibiting indoleamine 2,3-dioxygenase (IDO) is already an experimental strategy that has been used for treating certain types of cancer [89].…”

Section: Discussionmentioning

confidence: 99%

The Role of Tryptophan Metabolites in Musculoskeletal Stem Cell Aging

Anaya

Bollag

Hamrick

et al. 2020

IJMS

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Although aging is considered a normal process, there are cellular and molecular changes that occur with aging that may be detrimental to health. Osteoporosis is one of the most common age-related degenerative diseases, and its progression correlates with aging and decreased capacity for stem cell differentiation and proliferation in both men and women. Tryptophan metabolism through the kynurenine pathway appears to be a key factor in promoting bone-aging phenotypes, promoting bone breakdown and interfering with stem cell function and osteogenesis; however, little data is available on the impact of tryptophan metabolites downstream of kynurenine. Here we review available data on the impact of these tryptophan breakdown products on the body in general and, when available, the existing evidence of their impact on bone. A number of tryptophan metabolites (e.g., 3-hydroxykynurenine (3HKYN), kynurenic acid (KYNA) and anthranilic acid (AA)) have a detrimental effect on bone, decreasing bone mineral density (BMD) and increasing fracture risk. Other metabolites (e.g., 3-hydroxyAA, xanthurenic acid (XA), picolinic acid (PIA), quinolinic acid (QA), and NAD+) promote an increase in bone mineral density and are associated with lower fracture risk. Furthermore, the effects of other tryptophan breakdown products (e.g., serotonin) are complex, with either anabolic or catabolic actions on bone depending on their source. The mechanisms involved in the cellular actions of these tryptophan metabolites on bone are not yet fully known and will require further research as they are potential therapeutic targets. The current review is meant as a brief overview of existing English language literature on tryptophan and its metabolites and their effects on stem cells and musculoskeletal systems. The search terms used for a Medline database search were: kynurenine, mesenchymal stem cells, bone loss, tryptophan metabolism, aging, and oxidative stress.

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“…Fang et al [ 36 ] also disclosed the novel role of NAD + in autophagy and mitophagy. Altered KP activity impacts NAD + production thereby results in age associated diseases [ 37 ]. KP metabolites and enzyme derivatives have an impact on nicotinamide adenine dinucleotide phosphate (NADPH) synthesis and NMDA receptor-mediated transmission that may contribute to the degenerative changes of the aged persons [ 17 ].…”

Section: Impact Of Kp In Ageingmentioning

confidence: 99%

Kynurenine pathway in Parkinson's disease—An update

et al. 2020

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Parkinson's disease (PD) is a complex multi-factorial neurodegenerative disorder where various altered metabolic pathways contribute to the progression of the disease. Tryptophan (TRP) is a major precursor in kynurenine pathway (KP) and it has been discussed in various in vitro studies that the metabolites quinolinic acid (QUIN) causes neurotoxicity and kynurenic acid (KYNA) acts as neuroprotectant respectively. More studies are also focused on the effects of other KP metabolites and its enzymes as it has an association with ageing and PD pathogenesis. Until now, very few studies have targeted the role of genetic mutations in abnormal KP metabolism in adverse conditions of PD. Therefore, the present review gives an updated research studies on KP in connection with PD. Moreover, the review emphasizes on the urge for the development of biomarkers and also this would be an initiative in generating an alternative therapeutic approach for PD.

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Kynurenine pathway, NAD+ synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan

Cited by 183 publications

References 146 publications

Multifactorial Analysis of Environmental Metabolomic Data in Ecotoxicology: Wild Marine Mussel Exposed to WWTP Effluent as a Case Study

Multifactorial Analysis of Environmental Metabolomic Data in Ecotoxicology: Wild Marine Mussel Exposed to WWTP Effluent as a Case Study

The Role of Tryptophan Metabolites in Musculoskeletal Stem Cell Aging

Kynurenine pathway in Parkinson's disease—An update

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