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

BACKGRUOUND: 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, β=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.