@article{c37fa5bf2d234133b698927eaf718138,
title = "Kynurenines link chronic inflammation to functional decline and physical frailty",
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.",
author = "Reyhan Westbrook and Tae Chung and Jacqueline Lovett and Chris Ward and Humberto Joca and Huanle Yang and Mohammed Khadeer and Jing Tian and Xue, {Qian Li} and Anne Le and Luigi Ferrucci and Ruin Moaddel and {de Cabo}, Rafa and Ahmet Hoke and Jeremy Walston and Abadir, {Peter M.}",
note = "Funding Information: The authors would like to thank Robert Schwarcz and Francesca Notarangelo for thoughtful discussion and feedback. This study was supported by the Johns Hopkins Older Americans Independence Center National Institute on Aging (grants P30 AG021334) and NIH grants R01AG046441 and K23 AG035005, as well as by Bright Focus Foundation Research Award (PMA) and the Nathan W. and Margaret T. Shock Aging Research Foundation, Nathan Shock Scholar in Aging (PMA and RW), The American Federation for Aging Research (RW), Secunda Family Foundation (RW), K08 AG058483 (TC), R01 AR071618, P30-AG028747, Baltimore Veterans Affairs Medical Center Geriatric Education Clinical Center (GRECC) (CW), and the Miriam and Sheldon G. Adelson Medical Foundation (AH). It was supported, in part, by the Intramural Research Program of the National Institute on Aging. Publisher Copyright: Copyright: {\textcopyright} 2020, Westbrook et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",
year = "2020",
month = aug,
day = "20",
doi = "10.1172/jci.insight.136091",
language = "English (US)",
volume = "5",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "16",
}