scholarly journals Combating Age-Associated Immune Decline Using Kynurenine Pathway Interventions

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 678-679
Author(s):  
Luis Espejo ◽  
Destiny DeNicola ◽  
Sam Freitas ◽  
Hope Dang ◽  
Emily Turner ◽  
...  
Keyword(s):  
Immune Function ◽  
Potential Role ◽  
Pathogen Resistance ◽  
Kynurenine Pathway ◽  
C Elegans ◽  
Innate Immune Signaling ◽  
Aging Populations ◽  
Pathogen Response ◽  
Hydroxyanthranilic Acid ◽  
Invertebrate Models

Abstract Select kynurenine pathway interventions extend lifespan in invertebrate models and are of interest in treating age-associated diseases. Kynurenine pathway activity is responsive to inflammatory signaling, and we are evaluating the potential for these interventions to increase pathogen resistance and curtail age-associated immune decline in Caenorhabditis elegans and mammals. The kynurenine pathway facilitates the catabolism of tryptophan to nicotinamide adenine dinucleotide (NAD). Our lab has found that supplementing the kynurenine metabolite 3-hydroxyanthranilic acid (3HAA) or inhibiting the enzyme 3HAA dioxygenase (HAAO) extends lifespan in C. elegans. 3HAA has demonstrated pro/anti-inflammatory properties in mammals, suggesting a potential role in immune function. C. elegans have a primitive immune system that lacks an adaptive element, but it recapitulates aspects of innate immune signaling and pathogen response. I hypothesize kynurenine pathway interventions that impact C. elegans’ lifespan similarly improve pathogen resistance and immunity. Interventions within the kynurenine pathway are capable of differentially impacting pathogenesis and lifespan of C. elegans challenged with Psuedomonas aeruginosa. C. elegans subjected to select lifespan-extending kynurenine pathway interventions fared better when challenged with P. aeruginosa at older ages. Additionally, fluorescent infection tracking has displayed decreased infection rates in worms with elevated 3HAA. Our data suggests pro-immune activity is facilitated by 3HAA acting downstream of the dbl-1 pathway in addition to directly inhibiting bacterial growth. Our goal is to discover the mechanism(s) through which the kynurenine pathway interacts with immune function in animals and identify potential targets for clinical therapy in aging populations.

scholarly journals TARGETING TRYPTOPHAN-KYNURENINE METABOLISM TO EXTEND LIFESPAN AND TREAT AGE-ASSOCIATED DISEASE

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S616-S616
Author(s):  
George L Sutphin ◽  
George L Sutphin
Keyword(s):  
Cardiovascular Disease ◽  
Mechanistic Model ◽  
Kynurenine Pathway ◽  
C Elegans ◽  
Single Target ◽  
Extended Lifespan ◽  
Tryptophan Catabolism ◽  
Major Route ◽  
Kynurenine Metabolism ◽  
Hydroxyanthranilic Acid

Abstract The kynurenine pathway, the major route for tryptophan catabolism, becomes dysregulated with age and in many age-associated pathologies in humans. Interventions targeting kynurenine metabolism are being pursued for neurodegeneration, cardiovascular disease, and chronic kidney disease. By manipulating kynurenine pathway enzymes and metabolites, we have extended lifespan up to 40% in Caenorhabditis elegans. Our most promising single target is the metabolite 3-hydroxyanthranilic acid dioxygenase (3HAA). Elevating physiological 3HAA by directly supplementing 3HAA or inhibiting the enzyme 3HAA dioxygenase (HAAO) extends worm lifespan by ~30% while reducing oxidative stress by directly degrading hydrogen peroxide. In rodents, anti-inflammatory activity of 3HAA improves outcomes in models of cardiovascular disease, asthma, and autoimmune encephalomyelitis. We are now beginning to validate our C. elegans work in mice and investigating a mechanistic model in which 3HAA acts to extend healthy lifespan by slowing age-associated accumulation of oxidative damage and repressing chronic inflammation.

scholarly journals Targeting kynurenine metabolism to reduce inflammation and enhance stress response during aging

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 686-687
Author(s):  
George Sutphin ◽  
Hope Dang ◽  
Luis Espejo ◽  
Raul Castro-Portuguez ◽  
Bradford Hull ◽  
...  
Keyword(s):  
Stress Response ◽  
De Novo ◽  
Preliminary Evidence ◽  
Kynurenine Pathway ◽  
Cellular Stress Response ◽  
C Elegans ◽  
Extended Lifespan ◽  
Kynurenine Metabolism ◽  
Hydroxyanthranilic Acid ◽  
The Impact

Abstract Aberrant kynurenine pathway metabolism is increasingly linked to aging and age-associated disease. Kynurenine metabolic activity increases with age and becomes dysregulated during various forms of age-associated pathology in humans. By manipulating one or more kynurenine pathway enzymes and metabolites, we have extended lifespan up to 40% in Caenorhabditis elegans. In particular, elevating physiological levels of the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3HAA) by directly supplementing 3HAA or inhibiting the enzyme 3HAA dioxygenase (HAAO) extends C. elegans lifespan by ~30%. 3HAA delivered chronically in chow similarly extends lifespan in aged C57BL/6 mice. In ongoing work, we are investigating the mechanisms underlying the benefits of multiple kynurenine pathway interventions using tools in C. elegans, mice, and human cell culture. We have preliminary evidence for activation of broad-spectrum cellular stress response, enhanced immune function, and reduced inflammation. Among other roles, the kynurenine pathway is the sole metabolic route for de novo synthesis of nicotinamide adenine dinucleotide (NAD+) from tryptophan in Eukaryotic cells. We are examining the regulatory interaction between kynurenine metabolism and the two NAD+ recycling pathways, Salvage and Preiss-Handler, both as potential mechanistic mediators and as possible parallel targets for combined interventions with synergistic benefits in aging. We are further evaluating the impact of these interventions in several models of specific age-associated diseases, including sepsis, chronic inflammation, stroke, Alzheimer’s disease, and cancer. Finally, we are developing pharmaceutical strategies to replicate key genetic and metabolic interventions within the kynurenine pathway that can be readily translated into clinical applications.

scholarly journals Heat Stress Reduces the Susceptibility of Caenorhabditis elegans to Orsay Virus Infection

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1161
Author(s):  
Yuqing Huang ◽  
Mark G. Sterken ◽  
Koen van Zwet ◽  
Lisa van Sluijs ◽  
Gorben P. Pijlman ◽  
...  
Keyword(s):  
Heat Stress ◽  
Caenorhabditis Elegans ◽  
Virus Infection ◽  
Intracellular Pathogen ◽  
Potential Candidate ◽  
Molecular Responses ◽  
C Elegans ◽  
Pathogen Response ◽  
Orsay Virus ◽  
Natural Virus

The nematode Caenorhabditis elegans has been a versatile model for understanding the molecular responses to abiotic stress and pathogens. In particular, the response to heat stress and virus infection has been studied in detail. The Orsay virus (OrV) is a natural virus of C. elegans and infection leads to intracellular infection and proteostatic stress, which activates the intracellular pathogen response (IPR). IPR related gene expression is regulated by the genes pals-22 and pals-25, which also control thermotolerance and immunity against other natural pathogens. So far, we have a limited understanding of the molecular responses upon the combined exposure to heat stress and virus infection. We test the hypothesis that the response of C. elegans to OrV infection and heat stress are co-regulated and may affect each other. We conducted a combined heat-stress-virus infection assay and found that after applying heat stress, the susceptibility of C. elegans to OrV was decreased. This difference was found across different wild types of C. elegans. Transcriptome analysis revealed a list of potential candidate genes associated with heat stress and OrV infection. Subsequent mutant screens suggest that pals-22 provides a link between viral response and heat stress, leading to enhanced OrV tolerance of C. elegans after heat stress.

Potential role of protein stabilizers in amelioration of Parkinson's disease and associated effects in transgenic Caenorhabditis elegans model expressing alpha-synuclein

RSC Advances ◽  
2015 ◽  
Vol 5 (95) ◽  
pp. 77706-77715 ◽  
Author(s):  
Supinder Kaur ◽  
Aamir Nazir
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Caenorhabditis Elegans ◽  
Potential Role ◽  
Alpha Synuclein ◽  
C Elegans

Studies employing transgenicC. elegansmodel show that trehalose, a protein stabilizer, alleviates manifestations associated with Parkinson's diseaseviaits inherent activity and through induction of autophagic machinery.

scholarly journals The purine nucleoside phosphorylase pnp-1 regulates epithelial cell resistance to infection in C. elegans

2021 ◽  
Author(s):  
Eillen Tecle ◽  
Crystal B. Chhan ◽  
Latisha Franklin ◽  
Ryan S. Underwood ◽  
Wendy Hanna-Rose ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Purine Nucleoside Phosphorylase ◽  
Negative Regulator ◽  
Purine Nucleoside ◽  
Intracellular Pathogens ◽  
Intestinal Epithelial ◽  
Purine Nucleotides ◽  
Nucleoside Phosphorylase ◽  
C Elegans ◽  
Pathogen Response

AbstractIntestinal epithelial cells are subject to attack by a diverse array of microbes, including intracellular as well as extracellular pathogens. While defense in epithelial cells can be triggered by pattern recognition receptor-mediated detection of microbe-associated molecular patterns, there is much to be learned about how they sense infection via perturbations of host physiology, which often occur during infection. A recently described host defense response in the nematode C. elegans called the Intracellular Pathogen Response (IPR) can be triggered by infection with diverse natural intracellular pathogens, as well as by perturbations to protein homeostasis. From a forward genetic screen, we identified the C. elegans ortholog of purine nucleoside phosphorylase pnp-1 as a negative regulator of IPR gene expression, as well as a negative regulator of genes induced by extracellular pathogens. Accordingly, pnp-1 mutants have resistance to both intracellular and extracellular pathogens. Metabolomics analysis indicates that C. elegans pnp-1 likely has enzymatic activity similar to its human ortholog, serving to convert purine nucleosides into free bases. Classic genetic studies have shown how mutations in human purine nucleoside phosphorylase cause immunodeficiency due to T-cell dysfunction. Here we show that C. elegans pnp-1 acts in intestinal epithelial cells to regulate defense. Altogether, these results indicate that perturbations in purine metabolism are likely monitored as a cue to promote defense against epithelial infection in the nematode C. elegans.Author summaryAll life requires purine nucleotides. However, obligate intracellular pathogens are incapable of generating their own purine nucleotides and thus have evolved strategies to steal these nucleotides from host cells in order to support their growth and replication. Using the small roundworm C. elegans, we show that infection with natural obligate intracellular pathogens is impaired by loss of pnp-1, the C. elegans ortholog of the vertebrate purine nucleoside phosphorylase (PNP), which is an enzyme involved in salvaging purines. Loss of pnp-1 leads to altered levels of purine nucleotide precursors and increased expression of Intracellular Pathogen Response genes, which are induced by viral and fungal intracellular pathogens of C. elegans. In addition, we find that loss of pnp-1 increases resistance to extracellular pathogen infection and increases expression of genes involved in extracellular pathogen defense. Interestingly, studies from 1975 found that mutations in human PNP impair T-cell immunity, whereas our findings here indicate C. elegans pnp-1 regulates intestinal epithelial immunity. Overall, our work indicates that host purine homeostasis regulates resistance to both intracellular and extracellular pathogen infection.

scholarly journals An intracellular pathogen response pathway promotes proteostasis in C. elegans

2017 ◽  
Author(s):  
Kirthi C. Reddy ◽  
Tal Dror ◽  
Jessica N. Sowa ◽  
Johan Panek ◽  
Kevin Chen ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Intracellular Pathogen ◽  
Forward Genetic Screen ◽  
C Elegans ◽  
Transcriptional Signature ◽  
Proteotoxic Stress ◽  
Ubiquitin Ligase Complex ◽  
Pathogen Response ◽  
Mutant Phenotypes ◽  
Increased Activity

SummaryMaintenance of proteostasis is critical for organismal health. Here we describe a novel pathway that promotes proteostasis, identified through the analysis of C. elegans genes upregulated by intracellular infection. We named this distinct transcriptional signature the Intracellular Pathogen Response (IPR), and it includes upregulation of several predicted ubiquitin ligase complex components such as the cullin cul-6. Through a forward genetic screen we found pals-22, a gene of previously unknown function, to be a repressor of the cul-6/Cullin gene and other IPR gene expression. Interestingly, pals-22 mutants have increased thermotolerance and reduced levels of stress-induced polyglutamine aggregates, likely due to upregulated IPR expression. We found the enhanced stress resistance of pals-22 mutants to be dependent on cul-6, suggesting that pals-22 mutants have increased activity of a CUL-6/Cullin-containing ubiquitin ligase complex. pals-22 mutant phenotypes are distinct from the well-studied heat shock and insulin signaling pathways, indicating that the IPR is a novel pathway that protects animals from proteotoxic stress.

scholarly journals Serum profiles of tryptophan-kynurenine pathway metabolites in psoriasis

2021 ◽  
Author(s):  
Mariko Seishima ◽  
Yasuko Yamamoto ◽  
Masashi Sakurai ◽  
Rika Sakai ◽  
Kento Fujii ◽  
...  
Keyword(s):  
High Performance ◽  
Severity Index ◽  
Skin Lesions ◽  
Kynurenine Pathway ◽  
Psoriasis Area Severity Index ◽  
Systemic Inflammatory Disease ◽  
Cytokine Levels ◽  
Uninvolved Skin ◽  
Psoriasis Therapy ◽  
Hydroxyanthranilic Acid

Aim: Chronic inflammation is closely associated with tryptophan (TRP)-kynurenine (KYN) metabolic pathway. However, TRP-KYN pathway has not been fully elucidated in psoriasis, a systemic inflammatory disease with skin lesions and extracutaneous manifestations. Herein, we studied comprehensively serum profiles of TRP-KYN pathway metabolites in psoriatic patients (PSOs) to clarify the involvement of this pathway in the pathophysiology of psoriasis and to evaluate serum biomarkers reflecting systemic inflammation in PSOs. Methods: The concentrations of main TRP metabolites, TRP, KYN, 3-hydroxykynurenine (3HK), kynurenic acid (KYNA), 3-hydroxyanthranilic acid (3HAA), and anthranilic acid (AA), were determined by high-performance liquid chromatography in the sera from 65 PSOs and 35 healthy controls (HCs). The levels of these metabolites and the ratios of metabolites were compared between these subjects. The correlations between these values and the psoriasis area severity index (PASI) scores were analyzed. Skin samples from PSOs and HCs were subjected to immunohistochemical staining for kynureninase. Cytokine concentrations were comprehensively measured in the same samples and the correlations between the cytokine levels and TRP-KYN pathway metabolite levels were examined. Results: Serum TRP, KYN, and KYNA concentrations were lower and the 3HAA concentrations were higher in PSOs than in HCs. The ratios of 3HK/KYN, 3HAA/3HK, and 3HK/AA were higher in PSOs than in HCs. The AA levels and the ratio of AA/KYN were weakly positively correlated, and TRP, KYNA, and 3HK levels and the ratios of KYNA/KYN and 3HAA/AA were weakly negatively correlated with the PASI scores. The AA, KYN, and KYNA levels were positively correlated with the interferon gamma-induced protein 10 (IP-10) concentrations. Kynureninase expression was enhanced in the epidermis, both involved and uninvolved skin. Conclusions: Serum profiles of TRP-KYN pathway metabolites differed between PSOs and HCs. TRP-KYN pathway-associated processes, including kynureninase activation, may be involved in the pathogenesis of psoriasis, and thus serve as targets for psoriasis therapy.

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