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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-?R1 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.

SUBMITTER: Westbrook R

PROVIDER: S-EPMC7455140 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Kynurenines link chronic inflammation to functional decline and physical frailty.

Westbrook Reyhan R Chung Tae T Lovett Jacqueline J Ward Chris C Joca Humberto H Yang Huanle H Khadeer Mohammed M Tian Jing J Xue Qian-Li QL Le Anne A Ferrucci Luigi L Moaddel Ruin R de Cabo Rafa R Hoke Ahmet A Walston Jeremy J Abadir Peter M PM

JCI insight 20200820 16

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 incre ...[more]

PMID: 32814718

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Project description:Background Frailty is increasingly applied as a measure to predict clinical outcomes, but data on the predictive abilities of frailty measures for non-home discharge and functional decline in acutely hospitalized geriatric patients are scarce. Objectives The aim of this study was to investigate the predictive ability of the frailty phenotype and a frailty index currently validated as part of the ongoing Swiss Frailty Network and Repository Study based on clinical admission data for non-home discharge and functional decline in acutely hospitalized older patients. Design Prospective cohort study. Setting and Participants Data were analyzed from 334 consecutive hospitalized patients of a tertiary acute care geriatric inpatient clinic admitted between August 2020 and March 2021. Measurements We assessed frailty using 1) the frailty phenotype and 2) the Swiss Frailty Network and Repository Study (SFNR) frailty index based on routinely available clinical admission data. Predictive abilities of both frailty measures were analyzed for the clinical outcomes of non-home discharge and functional decline using multivariate logistic regression models and receiver operating characteristic curves (ROC). Results Mean age was 82.8 (SD 7.2) years and 55.4% were women. Overall, 170 (53.1%) were frail based on the frailty phenotype and 220 (65.9%) based on the frailty index. Frail patients based on the frailty phenotype were more likely to be discharged non-home (55 (32.4%) vs. 26 (17.3%); adjusted OR 2.4 (95% CI, 1.4, 5.1)). Similarly, frail patients based on the frailty index were more likely to be discharged non-home compared to non-frail patients (76 (34.6%) vs. 9 (7.9%); adjusted OR, 5.5 (95% CI, 2.6, 11.5)). Both, the frailty phenotype and the frailty index were similarly associated with functional decline (adjusted OR 2.7 (95% CI, 1.5, 4.9); adjusted OR 2.8 (95% CI 1.4, 5.5)). ROC analyses showed best discriminatory accuracy for the frailty index for non-home discharge (area under the curve 0.76). Conclusions Frailty using the SFNR-frailty index and the frailty phenotype is a promising measure for prediction of non-home discharge and functional decline in acutely hospitalized geriatric patients. Further study is needed to define the most valid frailty measure. Electronic Supplementary Material Supplementary material is available in the online version of this article at 10.14283/jfa.2022.44.

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Kynurenines link chronic inflammation to functional decline and physical frailty.

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Kynurenines link chronic inflammation to functional decline and physical frailty.

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