Kynurenines link chronic inflammation to functional decline and physical frailty

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere136091
JournalJCI Insight
Volume5
Issue number16
DOIs
StatePublished - Aug 20 2020

ASJC Scopus subject areas

  • Medicine(all)

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