Kynurenines link chronic inflammation to functional decline and physical frailty
Chronic inflammation is known to increase with aging. But the molecular mechanism that connects chronic inflammation to physical frailty and functional decline in older adults are yet to be elucidated. This was the aim of a research group led by Dr. Peter Abadir from the Division of Geriatric Medicine and Gerontology at the Johns Hopkins University in Baltimore, USA.
First, the researchers conducted metabolomic analyses using a mouse model of chronic inflammation. The mice showed reduced plasma levels of the essential amino acid tryptophan and elevated concentrations of the tryptophan degradation product kynurenine compared to control mice that did not have chronic inflammation. Consequently, the kynurenine/tryptophan ratio reflecting the activity of the rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO) converting tryptophan to kynurenine was increased in middle-aged and old pro-inflammatory mice compared to younger ones.
In a second step, these results were validated in human subjects, where frail older individuals showed even higher kynurenine/tryptophan ratios than non-frail ones. The ratio also correlated with levels of inflammatory cytokines like TNF-α, IFN-γ, and IL-6 that are known to induce IDO activity. In addition, lower levels of serotonin, another degradation product of tryptophan, were detected in serum from older individuals, independent from frailty, compared to younger adults. Furthermore, kynurenine metabolites known to have neurotoxic properties, 3-hydroxykynurenine and quinolinic acid, were elevated in both the frail subjects as well as frail and non-frail adults, respectively.
Together, accumulation of neurotoxic kynurenine metabolites with aging and, even more, with frailty could be identified as the mechanism of neuromuscular defects in older adults. Induction of IDO activity by inflammatory cytokines might be the underlying cause. The resulting degeneration of the motor nerve may be responsible for the decline in muscle mass and strength with aging. Besides alterations in the tryptophan metabolism, also changes in the arginine metabolism have been observed in this study which point towards kidney dysfunction in older adults.
This study not only identified a previously unclear molecular mechanism linking chronic inflammation to functional decline and physical frailty with aging, it is also an excellent example for the translatability of results from mouse to man.
If you want to learn more about the quatification of different tryptophan metabolites, please visit our webpage on the Tryptophan metabolism assay.
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Westbrook R, Chung T, Lovett J, Ward C, Joca H, Yang H et al. Kynurenines link chronic inflammation to functional decline and physical frailty. (2020) JCI Insight | https://doi.org/10.1172/jci.insight.136091