Association of markers of inflammation, the kynurenine pathway and B vitamins with age and mortality, and a signature of inflammaging

Abstract Background Inflammation is a key feature of aging. We aimed to i) investigate the association of 34 blood markers potentially involved in inflammatory processes with age and mortality, ii) develop a signature of ‘inflammaging’. Methods Thirty-four blood markers relating to inflammation, B vitamin status and the kynurenine pathway were measured in 976 participants in the Melbourne Collaborative Cohort Study at baseline (median age=59 years) and follow-up (median age=70 years). Associations with age and mortality were assessed using linear and Cox regression, respectively. A parsimonious signature of inflammaging was developed and its association with mortality was compared with two marker scores calculated across all markers associated with age and mortality, respectively. Results The majority of markers (30/34) were associated with age, with stronger associations observed for neopterin, cystatin C, IL-6, TNF-α, several markers of the kynurenine pathway and derived indices KTR (kynurenine/tryptophan ratio), PAr index (ratio of 4-pyridoxic acid and the sum of pyridoxal 5´-phosphate and pyridoxal), and HK:XA (3-hydroxykynurenine/xanthurenic acid ratio). Many markers (17/34) showed an association with mortality, in particular IL-6, neopterin, CRP, quinolinic acid, PAr index, and KTR. The inflammaging signature included ten markers and was strongly associated of mortality (HR per SD=1.40, 95%CI:1.24-1.57, P=2x10 -8), similar to scores based on all age-associated (HR=1.38, 95%CI:1.23-1.55, P=4x10 -8) and mortality-associated markers (HR=1.43, 95%CI:1.28-1.60, P=1x10 -10), respectively. Strong evidence of replication of the inflammaging signature association with mortality was found in the Hordaland Health Study. Conclusion Our study highlights the key role of the kynurenine pathway and vitamin B6 catabolism in aging, along with other well-established inflammation-related markers. A signature of inflammaging based on ten markers was strongly associated with mortality.

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876Association of blood markers of inflammation, vitamin status and the kynurenine pathway with age and all-cause mortality

International Journal of Epidemiology ◽

10.1093/ije/dyab168.174 ◽

2021 ◽

Vol 50 (Supplement_1) ◽

Author(s):

Pierre-antoine Dugué ◽

Allison Hodge ◽

Per Ueland ◽

Øivind Midttun ◽

Arve Ulvik ◽

...

Keyword(s):

Quinolinic Acid ◽

Cox Regression ◽

Strong Association ◽

Kynurenine Pathway ◽

Xanthurenic Acid ◽

Lasso Regression ◽

Markers Of Inflammation ◽

Par Index ◽

Vitamin Status ◽

All Cause Mortality

Abstract Background Inflammation is a key feature of aging and a cause of numerous diseases. We investigated the association of 35 blood markers involved in inflammatory processes with age and mortality and developed a signature of ‘inflammaging’. Methods Thirty-five blood markers relating to the kynurenine pathway, vitamin status, and inflammation were measured in 976 participants in the Melbourne Collaborative Cohort Study at baseline (1990-1994, median age 59 years) and follow-up (2003-2007, median age 70 years). Associations of each marker with age and all-cause mortality were assessed using linear and Cox regression, respectively. A signature of inflammaging was obtained via Lasso regression of age on the markers and tested for association with mortality; we compared mortality associations for this signature and two weighted scores across all markers associated with age and mortality, respectively. Results Most markers (29/35) were associated with age, with strongest associations observed for cystatin C, neopterin, quinolinic acid, and the kynurenine/tryptophan ratio, PAr index, and 3-hydroxykynurenine/xanthurenic acid ratio. Many markers (14/35) showed strong associations with mortality in particular neopterin, quinolinic acid, HK/XA, PAr index, CRP, IL-6 and KTr. The inflammaging signature included six markers and showed strong association with mortality (HR = 1.5, 95%CI: 1.3-1.7), almost as strong as the association of weighted scores combining all measured markers. Conclusions Our study highlights the key role played by markers of the kynurenine pathway and vitamin B6 catabolism in aging, along with other well-established inflammation-related markers. Key messages A signature of ‘inflammaging’ based on 6 markers may be useful to better predict mortality.

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Vitamins B2and B6as determinants of kynurenines and related markers of interferon-γ-mediated immune activation in the community-based Hordaland Health Study

British Journal Of Nutrition ◽

10.1017/s0007114514001858 ◽

2014 ◽

Vol 112 (7) ◽

pp. 1065-1072 ◽

Cited By ~ 29

Author(s):

Despoina Theofylaktopoulou ◽

Arve Ulvik ◽

Øivind Midttun ◽

Per Magne Ueland ◽

Stein Emil Vollset ◽

...

Keyword(s):

Immune Activation ◽

Plasma Concentrations ◽

Correlation Coefficients ◽

Interferon Γ ◽

Kynurenine Pathway ◽

Additive Models ◽

B Vitamins ◽

Health Study ◽

Xanthurenic Acid ◽

Hydroxyanthranilic Acid

Vitamins B2and B6are cofactors in the kynurenine pathway. Many of the kynurenines are neuroactive compounds with immunomodulatory effects. In the present study, we aimed to investigate plasma concentrations of vitamins B2and B6as determinants of kynurenines and two markers of interferon-γ-mediated immune activation (kynurenine:tryptophan ratio (KTR) and neopterin). We measured the concentrations of vitamins B2and B6vitamers, neopterin, tryptophan and six kynurenines (i.e. kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and xanthurenic acid) in plasma from 7051 individuals. Dietary intake of vitamins B2and B6was assessed using a validated FFQ. Associations were investigated using partial Spearman's correlations, generalised additive models, and segmented or multiple linear regression. The B2vitamer, riboflavin, was positively associated with 3-hydroxyanthranilic acid and xanthurenic acid, with correlation coefficients, as obtained by segmented regression, of 0·20 (95 % CI 0·16, 0·23) and 0·24 (95 % CI 0·19, 0·28), at riboflavin concentrations below the median value (13·0 nmol/l). The vitamin B6vitamer, pyridoxal 5′-phosphate (PLP), was positively associated with most kynurenines at PLP concentrations < 39·3–47·0 nmol/l, and inversely associated with 3-hydroxykynurenine with the association being more prominent at PLP concentrations < 18·9 nmol/l. Riboflavin and PLP were associated with xanthurenic acid only at relatively low, but normal concentrations of both vitamers. Lastly, PLP was negatively correlated with neopterin and KTR. These results demonstrate the significant and complex determination of kynurenine metabolism by vitamin status. Future studies on B-vitamins and kynurenines in relation to chronic diseases should therefore integrate data on relevant biomarkers related to B-vitamins status and tryptophan metabolism.

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Dietary Pattern Is Associated with Homocysteine and B Vitamin Status in an Urban Chinese Population

Journal of Nutrition ◽

10.1093/jn/133.11.3636 ◽

2003 ◽

Vol 133 (11) ◽

pp. 3636-3642 ◽

Cited By ~ 37

Author(s):

Xiang Gao ◽

Manjiang Yao ◽

Megan A. McCrory ◽

Guansheng Ma ◽

Yanping Li ◽

...

Keyword(s):

Dietary Pattern ◽

Chinese Population ◽

Vitamin Status ◽

B Vitamin

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P4-111: Longitudinal effects on cognitive function associated with homocysteine and B vitamin status in late adulthood

Alzheimer s & Dementia ◽

10.1016/j.jalz.2008.05.2177 ◽

2008 ◽

Vol 4 ◽

pp. T701-T701

Author(s):

Lawrence J. Whalley ◽

Kellie Rance ◽

Susan Duthie ◽

Helen Fox ◽

John Starr ◽

...

Keyword(s):

Cognitive Function ◽

Late Adulthood ◽

Vitamin Status ◽

Longitudinal Effects ◽

B Vitamin

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Coffee consumption and risk of renal cell carcinoma in the NIH-AARP Diet and Health Study

International Journal of Epidemiology ◽

10.1093/ije/dyab011 ◽

2021 ◽

Author(s):

Jongeun Rhee ◽

Erikka Loftfield ◽

Neal D Freedman ◽

Linda M Liao ◽

Rashmi Sinha ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Cox Regression ◽

Coffee Consumption ◽

Health Study ◽

Coffee Intake ◽

Decaffeinated Coffee ◽

Incident Cases ◽

Reduced Risk

Abstract Background Coffee consumption has been associated with a reduced risk of some cancers, but the evidence for renal cell carcinoma (RCC) is inconclusive. We investigated the relationship between coffee and RCC within a large cohort. Methods Coffee intake was assessed at baseline in the National Institutes of Health–American Association of Retired Persons Diet and Health Study. Among 420 118 participants eligible for analysis, 2674 incident cases were identified. We fitted Cox-regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for coffee consumption vs non-drinkers. Results We observed HRs of 0.94 (95% CI 0.81, 1.09), 0.94 (0.81, 1.09), 0.80 (0.70, 0.92) and 0.77 (0.66, 0.90) for usual coffee intake of <1, 1, 2–3 and ≥4 cups/day, respectively (Ptrend = 0.00003). This relationship was observed among never-smokers (≥4 cups/day: HR 0.62, 95% CI 0.46, 0.83; Ptrend = 0.000003) but not ever-smokers (HR 0.85, 95% CI 0.70, 1.05; Ptrend = 0.35; Pinteraction = 0.0009) and remained in analyses restricted to cases diagnosed >10 years after baseline (HR 0.65, 95% CI 0.51, 0.82; Ptrend = 0.0005). Associations were similar between subgroups who drank predominately caffeinated or decaffeinated coffee (Pinteraction = 0.74). Conclusion In this investigation of coffee and RCC, to our knowledge the largest to date, we observed a 20% reduced risk for intake of ≥2 cups/day vs not drinking. Our findings add RCC to the growing list of cancers for which coffee consumption may be protective.

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Ttrimetyllysine and risk of new-onset atrial fibrillation in two large norwegian cohorts

European Journal of Preventive Cardiology ◽

10.1093/eurjpc/zwab061.242 ◽

2021 ◽

Vol 28 (Supplement_1) ◽

Author(s):

MM Svenningsson ◽

I Dhar ◽

GFT Svingen ◽

EKR Pedersen ◽

D Nilsen ◽

...

Keyword(s):

Atrial Fibrillation ◽

Angina Pectoris ◽

Coronary Angiography ◽

Stable Angina ◽

Cox Regression ◽

Health Study ◽

Stable Angina Pectoris ◽

Age And Gender ◽

And Gender ◽

New Onset

Abstract Funding Acknowledgements Type of funding sources: None. Background/Aim Increased plasma trimetyllysine (TML), a methylated amino acid, has recently been linked to higher risk of acute myocardial infarction (AMI). TML is also a precursor of trimethylamine-N oxide (TMAO), which has been linked to increased cardiovascular risk, including that of atrial fibrillation (AF). We investigated the association between TML and new-onset AF in two large Norwegian cohorts. Methods The primary cohort consisted of 6396 participants in the community-based Hordaland Health Study (HUSK). The validation cohort consited of 2027 patients who underwent coronary angiography due to suspected stable angina pectoris in the Western Norway Coronary Angiography Cohort (WECAC). Information on new-onset AF was obtained by linking patient data to Norwegian public health registries. Risk associations were explored by Cox regression. Results During median (25th-75th percentile) follow-up of 10.9 (10.6-11.3) and 7.0 (6.3-8.6) years, 560 (8.8%) patients in the HUSK and 210 (10.4%) in the WECAC was diagnosed with AF. In the HUSK, the age and gender adjusted HR (95 % CI) for the 4th vs. 1st plasma TML quartiles 1.84 (1.37-2.48) p < 0.001. In multivariable models the association was only slightly attenuated. Correspondingsly, the age and gender adjusted HR (95% CI) for the 4th vs. 1st TML quartiles in the WECAC was 1.48 (0.96-2.27) p = 0.07. Testing for collinearity between TMAO and TML revealed variance inflation factors between 1.0-1.1 in HUSK and WECAC, thus ruling out collinearity. Conclusion Plasma TML was associated with new-onset AF among subjects from the general population, and the relationship was independent from established AF risk factors. A similar trend was also seen in patients with suspected stable angina pectoris, strengthening our findings, which motivate further studies to explore potential pathophysiological relationships between one-carbon metabolism and cardiac arrhythmias

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Clinical relevance of depressed kynurenine pathway in episodic migraine patients: potential prognostic markers in the peripheral plasma during the interictal period

The Journal of Headache and Pain ◽

10.1186/s10194-021-01239-1 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Bernadett Tuka ◽

Aliz Nyári ◽

Edina Katalin Cseh ◽

Tamás Körtési ◽

Dániel Veréb ◽

...

Keyword(s):

Anthranilic Acid ◽

Clinical Relevance ◽

Kynurenic Acid ◽

Picolinic Acid ◽

Plasma Concentrations ◽

Episodic Migraine ◽

Kynurenine Pathway ◽

Xanthurenic Acid ◽

Control Subjects ◽

Healthy Control

Abstract Background Altered glutamatergic neurotransmission and neuropeptide levels play a central role in migraine pathomechanism. Previously, we confirmed that kynurenic acid, an endogenous glutamatergic antagonist, was able to decrease the expression of pituitary adenylate cyclase-activating polypeptide 1–38, a neuropeptide with known migraine-inducing properties. Hence, our aim was to reveal the role of the peripheral kynurenine pathway (KP) in episodic migraineurs. We focused on the complete tryptophan (Trp) catabolism, which comprises the serotonin and melatonin routes in addition to kynurenine metabolites. We investigated the relationship between metabolic alterations and clinical characteristics of migraine patients. Methods Female migraine patients aged between 25 and 50 years (n = 50) and healthy control subjects (n = 34) participated in this study. Blood samples were collected from the cubital veins of subjects (during both the interictal/ictal periods in migraineurs, n = 47/12, respectively). 12 metabolites of Trp pathway were determined by neurochemical measurements (UHPLC-MS/MS). Results Plasma concentrations of the most Trp metabolites were remarkably decreased in the interictal period of migraineurs compared to healthy control subjects, especially in the migraine without aura (MWoA) subgroup: Trp (p < 0.025), L-kynurenine (p < 0.001), kynurenic acid (p < 0.016), anthranilic acid (p < 0.007), picolinic acid (p < 0.03), 5-hydroxy-indoleaceticacid (p < 0.025) and melatonin (p < 0.023). Several metabolites showed a tendency to elevate during the ictal phase, but this was significant only in the cases of anthranilic acid, 5-hydroxy-indoleaceticacid and melatonin in MWoA patients. In the same subgroup, higher interictal kynurenic acid levels were identified in patients whose headache was severe and not related to their menstruation cycle. Negative linear correlation was detected between the interictal levels of xanthurenic acid/melatonin and attack frequency. Positive associations were found between the ictal 3-hydroxykynurenine levels and the beginning of attacks, just as between ictal picolinic acid levels and last attack before ictal sampling. Conclusions Our results suggest that there is a widespread metabolic imbalance in migraineurs, which manifests in a completely depressed peripheral Trp catabolism during the interictal period. It might act as trigger for the migraine attack, contributing to glutamate excess induced neurotoxicity and generalised hyperexcitability. This data can draw attention to the clinical relevance of KP in migraine.

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