Kynurenines link chronic inflammation to functional decline and physical frailty
Author
Westbrook, ReyhanChung, 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
Date
2020-08-20Journal
JCI insightPublisher
American Society for Clinical InvestigationType
Article
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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.Identifier to cite or link to this item
http://hdl.handle.net/10713/13644ae974a485f413a2113503eed53cd6c53
10.1172/jci.insight.136091
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