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    Kynurenines link chronic inflammation to functional decline and physical frailty

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    Author
    Westbrook, Reyhan
    Chung, Tae
    Lovett, Jacqueline
    Ward, Chris
    Joca, Humberto
    Yang, Huanle
    Khadeer, Mohammed
    Tian, Jing
    Xue, Qian-Li
    Le, Anne
    Ferrucci, Luigi
    Moaddel, Ruin
    de Cabo, Rafa
    Hoke, Ahmet
    Walston, Jeremy
    Abadir, Peter M
    Show allShow less

    Date
    2020-08-20
    Journal
    JCI insight
    Publisher
    American Society for Clinical Investigation
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1172/jci.insight.136091
    Abstract
    Chronic inflammation is associated with physical frailty and functional decline in older adults; however, the molecular mechanisms of this linkage are not understood. A mouse model of chronic inflammation showed reduced motor function and partial denervation at the neuromuscular junction. Metabolomic profiling of these mice and further validation in frail human subjects showed significant dysregulation in the tryptophan degradation pathway, including decreased tryptophan and serotonin, and increased levels of some neurotoxic kynurenines. In humans, kynurenine strongly correlated with age, frailty status, TNF-αR1 and IL-6, weaker grip strength, and slower walking speed. To study the effects of elevated neurotoxic kynurenines on motor neuronal cell viability and axonal degeneration, we used motor neuronal cells treated with 3-hydroxykynurenine and quinolinic acid and observed neurite degeneration in a dose-dependent manner and potentiation of toxicity between 3-hydroxykynurenine and quinolinic acid. These results suggest that kynurenines mediate neuromuscular dysfunction associated with chronic inflammation and aging.
    Keyword
    Aging
    Cytokines
    Inflammation
    Neurodegeneration
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/13644
    ae974a485f413a2113503eed53cd6c53
    10.1172/jci.insight.136091
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