Higher Circulating Kynurenine Levels Linked to Higher Risk of Sarcopenia in Older Adults: A Cohort Study and UK Biobank Analysis

Abstract

Background: While experimental studies show kynurenine, a tryptophan metabolite, drives muscle catabolism through pro-oxidative and inflammatory mechanisms, clinical evidence linking circulating kynurenine to sarcopenia in humans remains scarce. Methods: In a cross-sectional study of 165 community-dwelling older adults, sarcopenia was diagnosed using Asian-specific criteria and serum kynurenine levels were measured by liquid chromatography-tandem mass spectrometry. Using UK Biobank datasets, plasma indoleamine 2,3-dioxygenase 1 (IDO1)-the enzyme converting tryptophan to kynurenine-was quantified via Olink proteomics, and Mendelian randomization was used to assess the causal effect of plasma IDO1 on sarcopenia risk based on genomewide association study data. Results: In multivariable adjusted analyses, older adults with sarcopenia, low muscle mass, or weak muscle strength had 21.3%- 29.2% higher serum kynurenine concentrations than controls (P<0.001 to 0.010). Circulating kynurenine levels were inversely correlated with skeletal muscle index and grip strength (P=0.001 and 0.022, respectively). Each standard deviation increase in serum kynurenine was associated with a 1.80-2.97-fold increased risk for sarcopenia-related outcomes (P<0.001 to 0.010). In the UK Biobank, higher IDO1 activity was associated with reduced muscle mass and strength (P=0.007 and P=0.004, respectively), and Mendelian randomization indicated a significant causal relationship between plasma IDO1 levels and increased sarcopenia risk (P= 0.010, beta=0.105). Conclusion: These findings extend previous experimental evidence to the clinical setting, suggesting that elevated kynurenine- driven by IDO1 activity-contributes to sarcopenia in older adults. Circulating kynurenine may serve as an exploratory biomarker candidate for identifying individuals at heightened risk for muscle deterioration, warranting further validation in future studies.