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Kynurenine Pathway Metabolites in the Blood and Cerebrospinal Fluid Are Associated with Human Aging

The kynurenine pathway is implicated in aging, longevity, and immune regulation, but longitudinal studies and assessment of the cerebrospinal fluid (CSF) are lacking. We investigated tryptophan (Trp) and downstream kynurenine metabolites and their associations with age and change over time in four c...

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Autores principales: Solvang, Stein-Erik H., Hodge, Allison, Watne, Leiv Otto, Cabral-Marques, Otavio, Nordrehaug, Jan Erik, Giles, Graham G., Dugué, Pierre-Antoine, Nygård, Ottar, Ueland, Per Magne, McCann, Adrian, Idland, Ane-Victoria, Midttun, Øivind, Ulvik, Arve, Halaas, Nathalie B., Tell, Grethe S., Giil, Lasse M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9616658/
https://www.ncbi.nlm.nih.gov/pubmed/36312896
http://dx.doi.org/10.1155/2022/5019752
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author Solvang, Stein-Erik H.
Hodge, Allison
Watne, Leiv Otto
Cabral-Marques, Otavio
Nordrehaug, Jan Erik
Giles, Graham G.
Dugué, Pierre-Antoine
Nygård, Ottar
Ueland, Per Magne
McCann, Adrian
Idland, Ane-Victoria
Midttun, Øivind
Ulvik, Arve
Halaas, Nathalie B.
Tell, Grethe S.
Giil, Lasse M.
author_facet Solvang, Stein-Erik H.
Hodge, Allison
Watne, Leiv Otto
Cabral-Marques, Otavio
Nordrehaug, Jan Erik
Giles, Graham G.
Dugué, Pierre-Antoine
Nygård, Ottar
Ueland, Per Magne
McCann, Adrian
Idland, Ane-Victoria
Midttun, Øivind
Ulvik, Arve
Halaas, Nathalie B.
Tell, Grethe S.
Giil, Lasse M.
author_sort Solvang, Stein-Erik H.
collection PubMed
description The kynurenine pathway is implicated in aging, longevity, and immune regulation, but longitudinal studies and assessment of the cerebrospinal fluid (CSF) are lacking. We investigated tryptophan (Trp) and downstream kynurenine metabolites and their associations with age and change over time in four cohorts using comprehensive, targeted metabolomics. The study included 1574 participants in two cohorts with repeated metabolite measurements (mean age at baseline 58 years ± 8 SD and 62 ± 10 SD), 3161 community-dwelling older adults (age range 71-74 years), and 109 CSF donors (mean age 73 years ± 7 SD). In the first two cohorts, age was associated with kynurenine (Kyn), quinolinic acid (QA), and the kynurenine to tryptophan ratio (KTR), and inversely with Trp. Consistent with these findings, Kyn, QA, and KTR increased over time, whereas Trp decreased. Similarly, QA and KTR were higher in community-dwelling older adults of age 74 compared to 71, whereas Trp was lower. Kyn and QA were more strongly correlated with age in the CSF compared to serum and increased in a subset of participants with repeated CSF sampling (n = 33) over four years. We assessed associations with frailty and mortality in two cohorts. QA and KTR were most strongly associated with mortality and frailty. Our study provides robust evidence of changes in tryptophan and kynurenine metabolism with human aging and supports links with adverse health outcomes. Our results suggest that aging activates the inflammation and stress-driven kynurenine pathway systemically and in the brain, but we cannot determine whether this activation is harmful or adaptive. We identified a relatively stronger age-related increase of the potentially neurotoxic end-product QA in brain.
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spelling pubmed-96166582022-10-29 Kynurenine Pathway Metabolites in the Blood and Cerebrospinal Fluid Are Associated with Human Aging Solvang, Stein-Erik H. Hodge, Allison Watne, Leiv Otto Cabral-Marques, Otavio Nordrehaug, Jan Erik Giles, Graham G. Dugué, Pierre-Antoine Nygård, Ottar Ueland, Per Magne McCann, Adrian Idland, Ane-Victoria Midttun, Øivind Ulvik, Arve Halaas, Nathalie B. Tell, Grethe S. Giil, Lasse M. Oxid Med Cell Longev Research Article The kynurenine pathway is implicated in aging, longevity, and immune regulation, but longitudinal studies and assessment of the cerebrospinal fluid (CSF) are lacking. We investigated tryptophan (Trp) and downstream kynurenine metabolites and their associations with age and change over time in four cohorts using comprehensive, targeted metabolomics. The study included 1574 participants in two cohorts with repeated metabolite measurements (mean age at baseline 58 years ± 8 SD and 62 ± 10 SD), 3161 community-dwelling older adults (age range 71-74 years), and 109 CSF donors (mean age 73 years ± 7 SD). In the first two cohorts, age was associated with kynurenine (Kyn), quinolinic acid (QA), and the kynurenine to tryptophan ratio (KTR), and inversely with Trp. Consistent with these findings, Kyn, QA, and KTR increased over time, whereas Trp decreased. Similarly, QA and KTR were higher in community-dwelling older adults of age 74 compared to 71, whereas Trp was lower. Kyn and QA were more strongly correlated with age in the CSF compared to serum and increased in a subset of participants with repeated CSF sampling (n = 33) over four years. We assessed associations with frailty and mortality in two cohorts. QA and KTR were most strongly associated with mortality and frailty. Our study provides robust evidence of changes in tryptophan and kynurenine metabolism with human aging and supports links with adverse health outcomes. Our results suggest that aging activates the inflammation and stress-driven kynurenine pathway systemically and in the brain, but we cannot determine whether this activation is harmful or adaptive. We identified a relatively stronger age-related increase of the potentially neurotoxic end-product QA in brain. Hindawi 2022-10-21 /pmc/articles/PMC9616658/ /pubmed/36312896 http://dx.doi.org/10.1155/2022/5019752 Text en Copyright © 2022 Stein-Erik H. Solvang et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Solvang, Stein-Erik H.
Hodge, Allison
Watne, Leiv Otto
Cabral-Marques, Otavio
Nordrehaug, Jan Erik
Giles, Graham G.
Dugué, Pierre-Antoine
Nygård, Ottar
Ueland, Per Magne
McCann, Adrian
Idland, Ane-Victoria
Midttun, Øivind
Ulvik, Arve
Halaas, Nathalie B.
Tell, Grethe S.
Giil, Lasse M.
Kynurenine Pathway Metabolites in the Blood and Cerebrospinal Fluid Are Associated with Human Aging
title Kynurenine Pathway Metabolites in the Blood and Cerebrospinal Fluid Are Associated with Human Aging
title_full Kynurenine Pathway Metabolites in the Blood and Cerebrospinal Fluid Are Associated with Human Aging
title_fullStr Kynurenine Pathway Metabolites in the Blood and Cerebrospinal Fluid Are Associated with Human Aging
title_full_unstemmed Kynurenine Pathway Metabolites in the Blood and Cerebrospinal Fluid Are Associated with Human Aging
title_short Kynurenine Pathway Metabolites in the Blood and Cerebrospinal Fluid Are Associated with Human Aging
title_sort kynurenine pathway metabolites in the blood and cerebrospinal fluid are associated with human aging
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9616658/
https://www.ncbi.nlm.nih.gov/pubmed/36312896
http://dx.doi.org/10.1155/2022/5019752
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