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Original ArticleHigher Circulating Kynurenine Levels Linked to Higher Risk of Sarcopenia in Older Adults: A Cohort Study and UK Biobank Analysis
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June Yeon Kim1*
, Yunju Jo2,3*, So Jeong Park4*, Ji Yeon Baek5, Geonyoung Jang5, Eunju Lee5, Hyuk Sakong4, Su Jung Kim6, Sung-Jin Kim1, Dongryeol Ryu2, Hyun Ju Yoo6, Beom-Jun Kim7 -
DOI: https://doi.org/10.3803/EnM.2025.2586
Published online: December 12, 2025
1Department of Oral Histology and Developmental Biology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
2Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
3Department of Microbiology, Wonkwang University School of Medicine, Iksan, Korea
4Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
5Division of Geriatrics, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
6Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
7Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Corresponding authors: Dongryeol Ryu. Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-gu, Gwangju 61005, Korea Tel: +82-62-715-5374, Fax: +82-62-715-5309, E-mail: dryu@gist.ac.kr
- Hyun Ju Yoo. Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel: +82-2-3010-4029, Fax: +82-2-2045-4146, E-mail: yoohyunju@amc.seoul.kr
- Beom-Jun Kim. Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel: +82-2-3010-5876, Fax: +82-2-3010-6962, E-mail: umkbj0825@amc.seoul.kr
- These authors contributed equally to this work.
• Received: August 1, 2025 • Revised: September 10, 2025 • Accepted: September 30, 2025
Copyright © 2025 Korean Endocrine Society
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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ABSTRACT
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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.
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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.
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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).
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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.
- Sarcopenia, characterized by an age-related, progressive decline in skeletal muscle mass and function, has emerged as a major public health challenge as the global population ages [1-3]. Beyond impairing strength and mobility, sarcopenia substantially increases the risks of frailty, falls, disability, and mortality, threatening the independence and quality of life in older adults [4,5]. Crucially, sarcopenia is now considered a potentially reversible or at least modifiable condition, and not merely an inevitable sequela of aging [6]. This evolving perspective underlines the urgent need to identify modifiable risk factors and robust, reliable biomarkers that allow for the early detection of individuals at high risk [7]. Timely intervention based on these markers is critical to prevent the onset or progression of sarcopenia and to support independent living among older adults. Consequently, the development and clinical validation of such biomarkers represent a pivotal step to reduce personal and societal burdens associated with sarcopenia [8].
- Emerging evidence has highlighted the role of metabolic pathways, particularly the tryptophan–kynurenine pathway (TKP), in muscle aging and sarcopenia [9]. Tryptophan, an essential amino acid, is primarily degraded through the TKP, resulting in the production of kynurenine, which has been shown to exert catabolic effects on skeletal muscle through pro-oxidative and inflammatory mechanisms [9-12]. Activation of this pathway, often driven by inflammatory cytokines via indoleamine 2,3-dioxygenase (IDO) activity, has been linked to muscle atrophy, reduced physical performance, and increased frailty risk [12-14]. Although animal studies and preliminary human data suggest that elevated kynurenine levels are associated with adverse musculoskeletal outcomes [15-17], clinical evidence directly linking the TKP to sarcopenia remains limited. To address this gap and elucidate the utility of circulating kynurenine and tryptophan as one of potential biomarkers of human muscle health, we investigated the association between their serum levels and sarcopenia, defined according to established diagnostic criteria, in a cohort of older adults.
INTRODUCTION
- Study population
- This observational study enrolled Korean adults aged 65 years or older who underwent comprehensive geriatric evaluations at the Division of Geriatrics or the Division of Endocrinology within the Department of Internal Medicine at Asan Medical Center (AMC) in Seoul, Korea, from May 2020 to March 2021. Eligible participants were community-dwelling, ambulatory individuals presenting to the outpatient clinic for non-specific symptoms such as fatigue or reduced appetite, or for management of chronic medical conditions including osteoarthritis, hypertension, or dyslipidemia. Exclusion criteria encompassed residence in long-term care institutions, current hospitalization, end-stage renal disease, active malignancy, and symptomatic heart failure associated with an estimated life expectancy under one year. A total of 165 participants who met the inclusion criteria provided written informed consent before participating in blood sampling and sarcopenia-related assessments during their clinic visit. The study protocol received approval from the Institutional Review Board of AMC (IRB No. 2020-0524) and was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki.
- Sarcopenia assessment
- Trained research personnel collected demographic and clinical data through structured interviews and a thorough review of electronic health records. Body composition, including appendicular skeletal muscle mass (ASM), was measured using multifrequency bioelectrical impedance analysis with the InBody S10 analyzer (InBody, Seoul, Korea), which utilizes frequencies of 1, 5, 50, 250, 500, and 1,000 kHz. ASM was calculated as the combined lean mass of both upper and lower limbs. The skeletal muscle mass index (SMI) was derived by dividing ASM by the square of the participant’s height (kg/m²).
- Muscle strength was determined by assessing handgrip strength in the dominant hand using a digital handheld dynamometer (Patterson Medical, Warrenville, IL, USA). Measurements were performed with participants seated and the elbow flexed at a 90° angle. Each participant completed two maximal voluntary contractions with a 1-minute rest interval, and the higher of the two readings was used for analysis. Physical performance was evaluated using three methods: usual gait speed over a 4-m walk, time to complete five consecutive chair rises, and the short physical performance battery (SPPB), which includes balance testing, gait speed, and repeated chair stands.
- Sarcopenia was diagnosed based on the 2019 consensus criteria established by the Asian Working Group for Sarcopenia, which requires reduced muscle mass in combination with either diminished strength or impaired physical performance [1]. Low muscle mass was defined as an SMI <7.0 kg/m² for men and <5.7 kg/m² for women. Weak muscle strength was indicated by handgrip strength values <28 kg in men and <18 kg in women. Criteria for poor physical performance included gait speed <1.0 m/sec, chair stand time >12 seconds, or an SPPB score ≤9.
- Serum kynurenine and tryptophan analysis
- Venous blood samples were collected in the morning following an overnight fast of at least 8 hours. Phlebotomy was performed at the antecubital vein using standard venipuncture techniques. Blood samples were immediately centrifuged at 3,000 revolutions per minute for 5 minutes at 4°C to isolate serum. Supernatant fractions were carefully extracted to eliminate cellular components. Samples exhibiting clot formation or visible hemolysis were excluded from further analysis. 50 μL human serum was mixed well and 50 μL of 2 μM tryptophan-d5 was added. Polar metabolites were extracted from aqueous phase by liquid-liquid extraction after adding 150 μL chloroform/methanol (2/1, v/v). The aqueous phase was used for chemical derivatization using 50 μL phenylisothiocyanate (PITC) derivatization solution (1,900 μL ethanol+1,900 μL H2O+1,900 μL pyridine+300 μL PITC). After the reaction, the derivatized kynurenine and tryptophan were extracted with 5 mM ammonium acetate in methanol, and ready for liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis. LC-MS/MS system was equipped with 1290 HPLC (Agilent, Santa Clara, CA, USA), Qtrap 5500 (ABSciex, Framingham, MA, USA), and Zorbax Eclipse XDB-C18 (100×2 mm) column. A 3 μL of sample solution was injected into the LC-MS/MS and ionized with turbo spray ionization source; 0.2% formic acid in H2O and 0.2% formic acid in acetonitrile were used as mobile phase A and B, respectively. The separation gradient was as follows: hold at 0% B for 0.5 minute, 0% to 95% B for 5 minutes, 95% B for 1 minute, and 95% to 0% B for 0.5 minute, then hold at 0% B for 2.5 minutes. LC flow was 500 μL/min, and column temperature was kept at 50°C. Multiple reaction monitoring was used in positive ion mode. Data analysis was performed by using Analyst 1.5.2 software (SCIEX, Marlborough, MA, USA), and the calibration range was 1 nM to 600 μM with R2>0.98.
- UK Biobank information
- UK Biobank is a large prospective epidemiological study designed to investigate the roles of genetic, lifestyle, and environmental factors in health and disease in mid-life to later life [18]. Sarcopenia was defined according to the criteria established by the European Working Group on Sarcopenia in Older People 2 (EWGSOP2); participants were classified as having sarcopenia if they met both the low muscle mass and low muscle strength criteria. Low muscle mass was defined as either ASM <20 kg or SMI <7.0 kg/m² for men, and ASM <15 kg or SMI <5.5 kg/m² for women [19]. Low muscle strength was defined as grip strength <27 kg for men and <16 kg for women. Individuals who met neither criterion were classified as non-sarcopenic, and those who met only one criterion were excluded from further analysis.
- We utilized plasma protein data from 54,219 UK Biobank participants, measured using Olink proteomics assays and reported as normalized protein expression (NPX) values on a log2 scale. Among these, NPX values for IDO1 and tryptophan 2,3-dioxygenase (TDO2) were extracted and analyzed. To facilitate comparability and interpretation, NPX values were standardized to z-scores prior to analysis.
- Genome-wide association study (GWAS) of single-variants was conducted for both binary and quantitative traits using SAIGE version 1.3.3 [20], which accounts for sample relatedness and case–control imbalance to control type I (error and maximize statistical power. All analyses were adjusted for sex, age, body mass index (BMI), and the first 10 genetic principal components (PC1–PC10). Following GWAS, clumping analysis was performed using PLINK version 1.9 to identify independent genome-wide significant loci, applying a significance threshold of P<5×10−8, a ±500 kb window, and a linkage disequilibrium (LD) threshold of r²>0.1.
- To investigate potential causal relationships between plasma protein levels and sarcopenia prevalence, Mendelian randomization (MR) analyses were performed using the TwoSampleMR and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) packages in R [21,22]. Genome-wide significant and LD-independent genetic variants (minor allele frequency [MAF] >0.01) located within the cis-region (±1 Mb) of the corresponding protein-coding gene were selected as instrumental variables. The inverse-variance weighted (IVW) method was used as the primary MR approach. Horizontal pleiotropy was assessed using the MR-PRESSO global test.
- Statistical analysis
- Continuous variables are presented as mean±standard deviations (SDs), and categorical variables as frequencies and percentages. Baseline characteristics between participants with and without sarcopenia were compared using Student’s t test for continuous variables and the chi-square (χ²) test for categorical variables. Differences in serum kynurenine and tryptophan levels and their ratio according to the presence of sarcopenia, low muscle mass, weak muscle strength, and poor physical performance were evaluated using analysis of covariance (ANCOVA), both before and after adjustment for potential confounders. The confounding variables—including sex, age, BMI, smoking, regular exercise, steroid use within the past 6 months, and serum creatinine and albumin levels—were selected based on their clinical relevance. Regular exercise was defined as engaging in moderate-intensity physical activity—characterized by a slight increase in breathing—at least three times per week. Linear regression analyses were performed to examine associations between serum kynurenine, tryptophan, and their ratio and sarcopenia-related muscle parameters, with and without adjustment for potential confounders. Logistic regression was used to estimate odds ratios (ORs) for the risk of sarcopenia and adverse muscle outcomes per 1-SD increase in serum kynurenine, tryptophan, and their ratio. Finally, differences in sarcopenia-related parameters across serum kynurenine quartiles were analyzed using ANCOVA. All statistical analyses were conducted using SPSS version 18.0 (SPSS Inc., Chicago, IL, USA), and a two-sided P value <0.05 was considered statistically significant.
- For statistical analysis using UK Biobank participant data, propensity score (PS) matching was performed between participants with and without sarcopenia to reduce potential confounding from baseline characteristics. PSs were estimated using logistic regression, with sarcopenia status as the outcome and sex, age, BMI, and PC1–PC10 as covariates. Nearest neighbor matching was conducted at a 1:4 case-to-control ratio without replacement using the MatchIt package in R version 4.7.2 (R Foundation for Statistical Computing, Vienna, Austria). Covariate balance before and after matching was assessed using standardized mean differences (SMDs), with an absolute SMD <0.1 considered indicative of acceptable balance. SMDs were calculated and visualized using the cobalt package in R version 4.6.0. In the matched sample, group differences in plasma IDO1 and TDO2 levels between participants with and without sarcopenia were evaluated using Student’s t tests. In addition, multiple linear regression was performed to assess associations between plasma IDO1 or TDO2 levels and continuous muscle-related outcomes, including ASM and grip strength. All models were adjusted for sex, age, BMI, and PC1–PC10, consistent with the covariates used in the PS estimation. Linear regression analyses were performed in R using the base lm() function.
METHODS
- Baseline characteristics according to sarcopenia status
- Baseline characteristics stratified by the presence or absence of sarcopenia are presented in Table 1. Among the total of 165 participants, women comprised 82.9% of those without sarcopenia (n=102) and 73.8% of those with sarcopenia (n=31), with no statistically significant difference between groups (P=0.257). Participants with sarcopenia were significantly older than those without (79.7±4.8 years vs. 75.2±5.2 years, P<0.001). Compared to the non-sarcopenic group, older adults with sarcopenia had significantly lower body weight, BMI, serum albumin, ASM, SMI, and handgrip strength (P<0.001 to 0.027). They also demonstrated slower gait speed and lower SPPB total score (both P<0.001). In the chair stand test, participants with sarcopenia required significantly more time to complete the task (P=0.003). Moreover, the sarcopenia phenotype score was higher among those with sarcopenia (P<0.001). However, there were no significant differences between groups in terms of height, serum creatinine, smoking status, regular exercise, prevalence of diabetes mellitus, polypharmacy, steroid use within the past 6 months, or history of falls in the previous year.
- Serum kynurenine and tryptophan levels by sarcopenia status and muscle phenotypes
- Differences in serum levels of kynurenine and tryptophan according to the presence of sarcopenia and its individual muscle phenotypes were analyzed using ANCOVA (Fig. 1). In the unadjusted model, serum kynurenine levels were significantly higher in individuals with sarcopenia (+29.8%), low muscle mass (+26.8%), and weak grip strength (+20.8%) compared to their respective counterparts without these conditions (P<0.001 to 0.008). These differences remained statistically significant even after adjustment for potential confounders, including sex, age, BMI, smoking, regular exercise, steroid use within the past 6 months, and serum creatinine and albumin levels (P<0.001 to 0.010). Similarly, the kynurenine-to-tryptophan ratio was at least 25% higher in participants with sarcopenia or low muscle mass than in those without, both before and after adjustment for confounding variables (P=0.001 to 0.003). In contrast, serum tryptophan levels did not significantly differ according to the presence or absence of sarcopenia, low muscle mass, weak muscle strength, or poor physical performance in either unadjusted or multivariable-adjusted models.
- Associations of serum kynurenine and tryptophan levels with muscle parameters
- The associations between serum kynurenine, tryptophan, and various muscle parameters were examined using linear regression analyses (Table 2). In univariate models, both serum kynurenine levels and the kynurenine-to-tryptophan ratio were negatively correlated with SMI, handgrip strength, and SPPB total score, while showing positive associations with chair stand time and the sarcopenia phenotype score (P<0.001 to 0.026). Additionally, the kynurenine-to-tryptophan ratio demonstrated a significant inverse association with the gait speed (P=0.046). Serum tryptophan levels, by contrast, were not significantly associated with most muscle parameters in unadjusted analyses, except for a weak negative correlation with chair stand time (P=0.045).
- After adjustment for sex, age, BMI, smoking, regular exercise, steroid use within the past 6 months, and serum creatinine and albumin levels, both serum kynurenine levels and the kynurenine-to-tryptophan ratio remained significantly associated with lower SMI and handgrip strength, and higher sarcopenia phenotype scores (P<0.001 to 0.022). The kynurenine-to-tryptophan ratio also showed a significant positive association with chair stand time and a negative association with SPPB total score in the multivariable-adjusted model (P=0.016 and P=0.040, respectively). However, serum tryptophan levels did not exhibit significant associations with any muscle-related parameters after multivariable adjustment.
- Risk of adverse muscle outcomes associated with elevated serum kynurenine and tryptophan levels
- The association between increasing serum levels of kynurenine, tryptophan, and the risk of adverse muscle outcomes was evaluated using logistic regression analysis (Table 3). In the unadjusted model, each one SD increase in serum kynurenine concentration was associated with a significantly higher odds of sarcopenia (OR, 2.10), low muscle mass (OR, 2.09), and weak muscle strength (OR, 1.62), with P values ranging from <0.001 to 0.011. These associations remained statistically significant after adjustment for potential confounders (P<0.001 to 0.010). Similarly, each 1-SD increase in the kynurenine-to-tryptophan ratio was associated with a 66% increased odds of sarcopenia (P=0.005) and a 74% increased odds of low muscle mass (P=0.003) in univariate analysis. These associations persisted in multivariable-adjusted models (P=0.010 and P=0.005, respectively). On the other hand, changes in serum tryptophan levels were not significantly associated with any adverse muscle outcomes in either unadjusted or adjusted models.
- Threshold effect of serum kynurenine levels on muscle parameters
- Given the stronger associations observed between serum kynurenine—rather than tryptophan—and adverse muscle parameters, we further explored a potential threshold effect by stratifying participants into quartiles based on serum kynurenine levels (Fig. 2). Compared with individuals in the lowest quartile (Q1, ≤2.66 μM), those in the highest quartile (Q4, ≥4.26 μM) exhibited significantly lower SMI, handgrip strength, and SPPB total scores by 8.4%, 14.6%, and 9.9%, respectively (P=0.003 to 0.028). However, gait speed and chair stand time did not significantly differ across quartile groups. After adjustment for sex, age, BMI, smoking, regular exercise, steroid use within the past 6 months, and serum creatinine and albumin levels, the between-group difference in SPPB total score was attenuated and no longer statistically significant. Nevertheless, participants in Q4 remained significantly associated with lower SMI and handgrip strength compared to those in Q1 (P=0.022 and P=0.042, respectively).
- Elevated plasma IDO1 is causally associated with sarcopenia in the UK Biobank
- To validate our clinical observation of elevated plasma kynurenine levels in individuals with sarcopenia, we next examined this association in a large population-based cohort—the UK Biobank. Because direct measurements of circulating kynurenine were not available in the UK Biobank dataset, we identified two key upstream enzymes—IDO1 and TDO2—that catalyze the rate-limiting step of the kynurenine pathway [23] and may serve as surrogate markers of its activity (Fig. 3A).
- Among the 437,277 UK Biobank participants with available muscle parameters and covariates, 2,761 were classified as having sarcopenia. Plasma proteomic measurements were obtained in a randomly selected subset of approximately 54,000 participants, within which IDO1 and TDO2 levels were available for 257 and 258 individuals with sarcopenia, respectively. To compare plasma protein levels while minimizing confounding, PS matching (1:4 nearest neighbor matching) was performed using sex, age, BMI, and PC1–PC10 as covariates (Supplemental Fig. S1). For each individual with sarcopenia, four non-sarcopenic individuals were selected from the pool of participants using nearest neighbor matching without replacement. The baseline clinical characteristics of the PS-matched participants, stratified by sarcopenia status, are summarized in Supplemental Tables S1, S2.
- Within the matched sample, plasma IDO1 levels were significantly higher in participants with sarcopenia compared to those without (P=0.039), whereas TDO2 levels did not differ significantly between groups (P=0.170) (Fig. 3B). Multiple linear regression analyses further revealed that higher IDO1 levels were significantly associated with lower ASM (P=0.007, β=–0.144) and reduced grip strength (P=0.004, β=–0.622) (Fig. 3C). In contrast, TDO2 levels were not significantly associated with either ASM (P=0.901) or grip strength (P=0.219) (Fig. 3D). Together, these findings indicate a more robust and consistent relationship between IDO1 and adverse muscle phenotypes compared to TDO2, and suggest that increased IDO1 activity may underlie the elevated kynurenine levels observed in sarcopenia, contributing to age-related muscle atrophy.
- To further assess the potential causal role of IDO1 in sarcopenia, we conducted a MR analysis using in-house GWAS summary statistics for plasma IDO1 levels derived from the UK Biobank. SAIGE analysis identified 125 independent cis-acting SNPs that were genome-wide significantly associated with plasma IDO1 levels (P<5×10−8) and had a MAF >0.01. These SNPs were used as instrumental variables for the IVW method (Table 4). MR analysis revealed a significant positive causal effect of plasma IDO1 level on sarcopenia risk (P=0.010, β=0.105). Notably, the MR-PRESSO global test did not detect evidence of horizontal pleiotropy (P=0.92), supporting the robustness of the causal inference. These findings suggest that genetically elevated plasma IDO1 levels may play a causal role in the development of sarcopenia in the general population.
RESULTS
- In this cohort study of ambulatory, community-dwelling older adults, we investigated the associations between serum tryptophan and kynurenine concentrations and sarcopenia defined by internationally accepted criteria, as well as its constituent muscle phenotypes. After adjusting for sex, age, BMI, smoking, regular exercise, steroid use within the past 6 months, and serum creatinine and albumin levels, our analysis demonstrated that participants with sarcopenia, low muscle mass, and reduced muscle strength exhibited at least 21% higher circulating kynurenine levels compared to those without these conditions. Moreover, elevated serum kynurenine concentrations were significantly associated with an increased risk of sarcopenia and adverse muscle outcomes. In contrast, circulating tryptophan—the precursor of kynurenine—was not significantly correlated with any measured muscle parameters. Importantly, leveraging data from the UK Biobank, the largest health cohort worldwide, we provide evidence that increased IDO1 activity, which catalyzes the conversion of tryptophan to kynurenine, is inversely associated with muscle mass and strength. These findings translate prior experimental evidence on kynurenine’s harmful effects on muscle metabolism to the clinical setting, supporting its potential utility as an exploratory biomarker candidate for identifying individuals at high risk of sarcopenia.
- A growing body of evidence highlights the critical role of chronic low-grade inflammation—commonly referred to as ‘inflammaging’—in the pathogenesis of age-related functional decline, including sarcopenia [24]. Within this context, the TKP has emerged as a key metabolic axis linking inflammation to musculoskeletal deterioration, particularly in aging skeletal muscle [9,14]. Preclinical studies have demonstrated that elevated kynurenine, a major metabolite of the TKP, exerts direct deleterious effects on muscle tissue, including induction of muscle atrophy, increased oxidative stress, lipid peroxidation, and disruption of mitochondrial function, as shown by both in vitro myoblast assays and in vivo animal models [11-13]. Additionally, kynurenine impacts bone marrow stromal cells, promoting cellular senescence and impairing differentiation critical to bone and muscle integrity [25-27]. Despite the robust and consistent evidence from experimental models, human studies directly examining the relationship between circulating kynurenine levels and sarcopenia—an archetypal aging phenotype defined by international consensus—have been lacking. Our study therefore fills a critical knowledge gap by demonstrating a significant and consistent association between higher serum kynurenine concentrations and adverse muscle phenotypes in older adults. These results not only validate previous mechanistic insights in human populations, but also underscore the potential clinical relevance of the kynurenine pathway in sarcopenia pathophysiology.
- The enzymatic conversion of tryptophan to kynurenine is primarily mediated by two distinct enzymes: IDO1 and TDO [9]. While TDO is constitutively expressed in the liver and mainly involved in systemic tryptophan homeostasis [23,28], IDO1 is inducible and broadly expressed across peripheral tissues, including immune cells and skeletal muscle [29]. Notably, IDO1 is activated in response to pro-inflammatory cytokines such as interferon-γ and tumor necrosis factor-α (TNF-α), which are elevated during the aging process and contribute to inflammaging [30,31]. Given that sarcopenia is closely linked to chronic low-grade inflammation and muscle-localized metabolic changes [32], kynurenine accumulation driven by IDO1 activity is more likely to play a central role in muscle degradation than the hepatic-centric actions mediated by TDO. Supporting this hypothesis, our complementary analysis using data from the UK Biobank demonstrated that elevated plasma IDO1 levels, rather than TDO levels, were significantly associated with lower muscle mass and reduced handgrip strength in a large population. Moreover, MR analysis revealed that genetically predicted higher IDO1 activity confers an increased risk and likely causal effect for sarcopenia. These results further substantiate the notion that IDO1-driven kynurenine accumulation may be one of the key mechanistic contributors to muscle atrophy in aging populations and reinforce the potential of targeting this metabolic axis for early identification and prevention of sarcopenia.
- Resistance exercise training is currently recognized as the most effective intervention for the prevention and treatment of sarcopenia [33]. Therefore, its potential interaction with the TKP represents an intriguing area of investigation. Accumulating evidence suggests that exercise, particularly resistance training, may beneficially modulate the TKP. Resistance exercise has been shown to reduce systemic inflammation and oxidative stress [34,35], both of which are critical activators of IDO1, the rate-limiting enzyme responsible for converting tryptophan to kynurenine [9,30,31]. By attenuating chronic low-grade inflammation, resistance training may downregulate IDO1 activity, thereby reducing kynurenine accumulation and attenuating its detrimental effects on skeletal muscle metabolism. Although direct clinical evidence linking resistance training to modulation of the TKP remains limited, these findings raise the possibility that exercise interventions could act synergistically with metabolic regulation of the kynurenine pathway to reduce sarcopenia progression. Future longitudinal and mechanistic studies are warranted to further clarify the interplay between resistance exercise, TKP activity, and muscle health in aging populations.
- A particularly intriguing finding in our study was that, although elevated serum kynurenine levels were significantly associated with decreased muscle mass and strength, they did not show a statistically significant association with physical performance. This discrepancy may be explained by the multifactorial nature of physical performance, which extends beyond mere muscle quantity and strength. Physical performance incorporates complex physiological domains such as neuromuscular coordination, balance, endurance capacity, cardiovascular fitness, and even psychological factors, all of which are not solely determined by muscle health or metabolism [36-38]. Similarly, a prior study on serum resistin levels demonstrated that while resistin was inversely associated with muscle mass and strength, its relationship with physical performance lost statistical significance after adjusting for key confounders [39]. This suggests that circulating biomarkers like kynurenine and resistin may primarily reflect direct effects on muscle tissue metabolism and function, but may not fully capture the broader integrative processes underlying physical performance. Therefore, while serum kynurenine may serve as a potential indicator of muscle atrophy, its utility in predicting functional impairment may be limited.
- The use of UK Biobank data and MR analysis adds important strengths to our study. UK Biobank provides an exceptionally large and well-characterized population-based cohort with extensive genomic, phenotypic, and health outcome data, enabling robust evaluation of epidemiological relationships in aging populations [40,41]. Moreover, MR employs the random allocation of genetic variants to infer causal relationships while minimizing confounding and reverse causality [42,43]. Importantly, our study not only demonstrated a strong association between serum kynurenine levels and sarcopenia-related muscle parameters in older adults, but also extended these findings by providing evidence for a causal relationship between genetically predicted IDO1 activity—a key upstream regulator of the kynurenine pathway—and both poor muscle parameters and increased risk of sarcopenia. This dual approach uniquely supports the concept that IDO1-mediated activation and resultant kynurenine elevation may directly contribute to skeletal muscle deterioration in humans, setting our findings apart from prior associative or preclinical studies.
- Despite the strengths of our study, several limitations should be acknowledged when interpreting the findings. First and most importantly, the cross-sectional design precludes conclusions regarding temporal sequence or directionality; our data reflect associations rather than cause-and-effect relationships. Although we attempted to strengthen the inference of causality through MR using UK Biobank data, prospective longitudinal studies are needed to determine whether baseline circulating kynurenine levels can predict the future development of sarcopenia. Second, based on prior experimental studies highlighting the role of kynurenine in muscle metabolism, we focused primarily on serum kynurenine concentrations. However, other tryptophan metabolites—such as kynurenic acid and quinolinic acid—may also be biologically active and potentially relevant to human muscle health, but were not evaluated in this study. Third, our cohort lacked data on inflammatory diseases and cytokines such as TNF-α and interleukin-6, preventing us from fully elucidating whether elevated kynurenine levels are a direct consequence of chronic inflammation or whether its effects on muscle homeostasis are mediated through inflammatory pathways. Fourth, Olink proteomics in the UK Biobank provides only relative quantification, is restricted to a predefined protein panel, and may introduce platform-specific bias. Fifth, differences in cohort characteristics between the Korean and predominantly European UK Biobank populations may limit the comparability of findings across cohorts. Lastly, although we have considered as many confounders as possible in our analysis, we cannot fully rule out the possibility that our results may have been influenced by unmeasured or residual confounding.
- In conclusion, this study of older adults aged 65 years and above demonstrated that higher serum kynurenine levels were independently associated with increased risks of sarcopenia, reduced muscle mass, and diminished strength after adjustment for key confounders. Furthermore, incorporating data from UK Biobank, we showed that greater IDO1 activity—an upstream contributor to kynurenine production—was linked to poorer muscle parameters and heightened sarcopenia risk. These findings provide clinical evidence supporting the deleterious impact of kynurenine on muscle metabolism, consistent with prior experimental research. Our results lay an important foundation for future longitudinal studies to determine whether serum kynurenine may serve as a predictive marker for the onset and progression of sarcopenia.
DISCUSSION
Supplementary Material
Supplemental Table S1.
Supplemental Table S2.
Supplemental Fig. S1.
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CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
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ACKNOWLEDGMENTS
This research was supported by grants from the Korean ARPAH Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (Grant No. RS-2024-00507256); the Korea Health Technology R&D Project through KHIDI, funded by the Ministry of Health and Welfare, Republic of Korea (Grant No. RS-2024-00401934); the Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea (grant number: 2022IP0036); the National Research Foundation (NRF), funded by the Korea Ministry of Science and ICT, Republic of Korea (Grandt No. RS-2024-00399341); and the NRF, funded by the Korea Ministry of Science, Republic of Korea (MSIT) (Grandt No. RS-2023-NR077276). This study was also supported by the Korean Endocrine Society of KES Research Award 2024. This research was conducted using the UK Biobank resource under Application Number 45227. We thank Professor Seunggeun Lee (Graduate School of Data Science, Seoul National University) for granting access to the data.
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AUTHOR CONTRIBUTIONS
Conception or design: J.Y.K., Y.J., S.J.P., D.R., H.J.Y., B.J.K. Acquisition, analysis, or interpretation of data: J.Y.K., Y.J., S. J.P., J.Y.B., G.J., E.L., H.S., S.J.K. (Su Jung Kim), S.J.K. (Sung- Jin Kim), D.R., H.J.Y., B.J.K. Drafting the work or revising: J.Y.K., Y.J., S.J.P., D.R., H.J.Y., B.J.K. Final approval of the manuscript: J.Y.K., Y.J., S.J.P., J.Y.B., G.J., E.L., H.S., S.J.K. (Su Jung Kim), S.J.K. (Sung-Jin Kim), D.R., H.J.Y., B.J.K.
Article information
Fig. 1.Differences in serum levels of kynurenine (Kyn) and tryptophan (Tryp) and their ratio based on sarcopenia status and the related parameters (A) before and (B) after adjusting for potential confounders. The multivariable adjustment model includes sex, age, body mass index, smoking, exercise, steroid use within the past 6 months, and serum creatinine and albumin levels. The estimated means with 95% confidence intervals were generated and compared using analysis of covariance. aStatistically difference from the control.
Fig. 2.Differences in sarcopenia components based on serum kynurenine quartiles (A) before and (B) after adjusting for potential confounders. The multivariable adjustment model includes sex, age, body mass index, smoking, exercise, steroid use within the past 6 months, and serum creatinine and albumin levels. The estimated means with 95% confidence intervals were generated and compared using analysis of covariance. Serum kynurenine quartiles: Q1=1.30–2.66 μM; Q2=2.67–3.35 μM; Q3=3.36–4.25 μM; Q4=4.26–9.42 μM. SMI, skeletal muscle mass index; SPPB, short physical performance battery. aStatistically significant difference from the lowest quartile (Q1).
Fig. 3.Plasma kynurenine pathway proteins and their associations with sarcopenia and related traits. (A) Schematic representation of the kynurenine biosynthesis pathway. Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) catalyze the conversion of tryptophan to kynurenine. (B) Comparison of plasma IDO1 and TDO2 levels between control and sarcopenia groups following 1:4 propensity score matching based on sex, age, body mass index (BMI), and genetic principal components (PCs). Matching was constrained to individuals of the same sex. Differences between the two groups were assessed using Student’s t tests. (C, D) Partial regression plots showing the association of plasma IDO1 (C) and TDO2 (D) levels with appendicular skeletal muscle mass (ASM) and grip strength in the matched population. Residuals from linear models adjusted for sex, age, BMI, and PCs are plotted on both axes. P values indicate the significance of the adjusted protein effect, and β coefficients represent the estimated effect size from the multiple linear regression. NS, not significant. aStatistically significant difference compared to the non-sarcopenia group.
Table 1.Basic Clinical Characteristics of the Study Participants
| Characteristic | No sarcopenia (n=123) | Sarcopenia (n=42) | P value |
|---|---|---|---|
| Female sex | 102 (82.9) | 31 (73.8) | 0.257 |
| Age, yr | 75.2±5.2 | 79.7±4.8 | <0.001a |
| Body weight, kg | 59.6±9.5 | 53.5±5.6 | <0.001a |
| Height, cm | 154.9±6.5 | 153.0±6.8 | 0.113 |
| Body mass index, kg/m2 | 25.4±5.4 | 22.9±2.5 | 0.004 |
| Serum albumin, g/dL | 3.95±0.24 | 3.85±0.27 | 0.027 |
| Serum creatinine, mg/dL | 0.86±0.33 | 0.83±0.21 | 0.631 |
| Smoking | 19 (15.4) | 5 (11.9) | 0.510 |
| Regular exercise | 18 (14.6) | 3 (7.1) | 0.173 |
| Diabetes mellitus | 48 (39.0) | 14 (33.3) | 0.582 |
| Polypharmacy | 63 (51.2) | 26 (61.9) | 0.283 |
| Steroid use within the past 6 months | 4 (3.3) | 3 (7.1) | 0.372 |
| Fall in previous year | 22 (17.9) | 8 (19.0) | 0.821 |
| Appendicular skeletal muscle mass, kg | 15.2±2.9 | 13.1±2.2 | <0.001a |
| Skeletal muscle mass index, kg/m2 | 6.31±0.79 | 5.55±0.52 | <0.001a |
| Grip strength, kg | 25.9±6.2 | 19.8±5.0 | <0.001a |
| Usual gait speed, m/sec | 1.04±0.23 | 0.78±0.26 | <0.001a |
| Chair stand test time, sec | 10.5±5.4 | 17.0±13.2 | 0.003a |
| SPPB total score (ranges, 0–12) | 10.9±1.6 | 8.3±3.1 | <0.001a |
| Sarcopenia phenotype score (range, 0–3) | 0.72±0.56 | 2.38±0.49 | <0.001a |
Table 2.Linear Regression Analysis to Determine the Association of Serum Kynurenine and Tryptophan Levels and Their Ratio with Muscle-Related Parameters
| Variable |
Serum kynurenine level |
Serum tryptophan level |
Serum KTR |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| β | SE | β | P value | β | SE | β | P value | β | SE | β | P value | |
| Unadjusted | ||||||||||||
| Skeletal muscle index | –0.181a | 0.045a | –0.302a | <0.001a | 0.004 | 0.003 | 0.100 | 0.201 | –13.6a | 3.280a | –0.310a | <0.001a |
| Grip strength | –1.298a | 0.369a | –0.265a | 0.001a | 0.031 | 0.022 | 0.106 | 0.174 | –103.9a | 26.9a | –0.290a | <0.001a |
| Chair stand | 1.222a | 0.497a | 0.190a | 0.015a | –0.060a | 0.030a | –0.157a | 0.045a | 112.5a | 36.1a | 0.238a | 0.002a |
| Gait speed | –0.022 | 0.016 | –0.108 | 0.169 | 0.001 | 0.001 | 0.120 | 0.127 | –2.289a | 1.139a | –0.156a | 0.046a |
| SPPB total score | –0.295a | 0.131a | –0.174a | 0.026a | 0.013 | 0.008 | 0.133 | 0.090 | –25.1a | 9.574a | –0.202a | 0.010a |
| SPS | 0.200a | 0.051 | 0.294a | <0.001a | –0.002 | 0.003 | –0.058 | 0.457 | 12.6a | 3.796a | 0.253a | 0.001a |
| Multivariable-adjusted | ||||||||||||
| Skeletal muscle index | –0.112a | 0.033a | –0.186a | 0.001a | 0.002 | 0.002 | 0.046 | 0.423 | –8.920a | 2.489a | –0.203a | <0.001a |
| Grip strength | –0.704a | 0.305a | –0.144a | 0.022a | 0.010 | 0.018 | 0.035 | 0.578 | –58.0a | 22.9a | –0.162a | 0.012a |
| Chair stand | 0.724 | 0.481 | 0.112 | 0.134 | –0.052 | 0.029 | –0.137 | 0.069 | 87.3a | 35.9a | 0.185a | 0.016a |
| Gait speed | –0.011 | 0.015 | –0.056 | 0.461 | 0.001 | 0.001 | 0.114 | 0.135 | –1.644 | 1.130 | –0.112 | 0.148 |
| SPPB total score | –0.194 | 0.126 | –0.114 | 0.127 | 0.012 | 0.008 | 0.124 | 0.101 | –19.7a | 9.483a | –0.158a | 0.040a |
| SPS | 0.153a | 0.049a | 0.225a | 0.002a | –0.002 | 0.003 | –0.046 | 0.536 | 10.2a | 3.707a | 0.205a | 0.006a |
The Enter method was applied to this model. The multivariable adjustment model includes sex, age, body mass index, smoking, exercise, steroid use within the past 6 months, and serum creatinine and albumin levels.
KTR, kynurenine/tryptophan ratio; β, unstandardized regression coefficient; SE, standard error; β, standardized regression coefficient; SPPB, short physical performance battery; SPS, sarcopenia phenotype score.
a Statistically significant values.
Table 3.Logistic Regression Analyses to Determine the Odds Ratios for Sarcopenia and the Related Parameters according to the Increase in Serum Kynurenine and Tryptophan Levels and Their Ratio
| Variable | OR (95% CI) per serum kynurenine SD increment | P value | OR (95% CI) per serum tryptophan SD increment | P value | OR (95% CI) per serum KTR SD increment | P value |
|---|---|---|---|---|---|---|
| Unadjusted | ||||||
| Sarcopenia | 2.10 (1.43–3.07)a | <0.001a | 0.98 (0.69–1.39) | 0.906 | 1.66 (1.17–2.35)a | 0.005a |
| Low muscle mass | 2.09 (1.44–3.05)a | <0.001a | 1.03 (0.75–1.40) | 0.871 | 1.74 (1.21–2.51)a | 0.003a |
| Weak muscle strength | 1.62 (1.12–2.36)a | 0.011a | 1.12 (0.75–1.67) | 0.574 | 1.32 (0.92–1.89) | 0.127 |
| Poor physical performance | 1.12 (0.82–1.53) | 0.469 | 0.74 (0.53–1.02) | 0.065 | 1.28 (0.92–1.79) | 0.143 |
| Multivariable-adjusted | ||||||
| Sarcopenia | 2.31 (1.45–3.71)a | <0.001a | 1.01 (0.65–1.58) | 0.954 | 1.78 (1.15–2.75)a | 0.010a |
| Low muscle mass | 2.97 (1.68–5.22)a | <0.001a | 1.12 (0.75–1.66) | 0.576 | 2.21 (1.27–3.86)a | 0.005a |
| Weak muscle strength | 1.80 (1.15–2.81)a | 0.010a | 1.14 (0.70–1.84) | 0.595 | 1.45 (0.95–2.24) | 0.087 |
| Poor physical performance | 0.97 (0.69–1.37) | 0.872 | 0.75 (0.53–1.08) | 0.121 | 1.12 (0.79–1.61) | 0.522 |
The multivariable adjustment model includes sex, age, body mass index, smoking, exercise, steroid use within the past 6 months, and serum creatinine and albumin levels.
OR, odds ratio; CI, confidence interval; SD, standard deviation; KTR, kynurenine/tryptophan ratio.
a Statistically significant values.
Table 4.Mendelian Randomization Analysis of the Causal Effect of Plasma IDO1 Protein Levels on Sarcopenia Risk Using UK Biobank GWAS Data
| Exposure | Outcome | MR method | nSNPs | Beta | SE | P value | MR-PRESSO global test P value |
|---|---|---|---|---|---|---|---|
| Plasma IDO1 level | Sarcopenia prevalence | Inverse-variance weighted | 125 | 0.105a | 0.040a | 0.010a | 0.92 |
MR was performed to assess the causal relationship between plasma IDO1 protein levels and sarcopenia prevalence using summary statistics from an inhouse GWAS of the UK Biobank. Only cis-acting genetic variants (cis-SNPs) were used as instrumental variables. The MR-PRESSO global test was applied to assess horizontal pleiotropy.
IDO1, indoleamine 2,3-dioxygenase 1; GWAS, genome-wide association study; MR, Mendelian randomization; nSNP, number of single nucleotide polymorphism; SE, standard error; MR-PRESSO, Mendelian Randomization Pleiotropy RESidual Sum and Outlier.
a Statistically significant values.
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XML DownloadHigher Circulating Kynurenine Levels Linked to Higher Risk of Sarcopenia in Older Adults: A Cohort Study and UK Biobank Analysis
Fig. 1. Differences in serum levels of kynurenine (Kyn) and tryptophan (Tryp) and their ratio based on sarcopenia status and the related parameters (A) before and (B) after adjusting for potential confounders. The multivariable adjustment model includes sex, age, body mass index, smoking, exercise, steroid use within the past 6 months, and serum creatinine and albumin levels. The estimated means with 95% confidence intervals were generated and compared using analysis of covariance. aStatistically difference from the control.
Fig. 2. Differences in sarcopenia components based on serum kynurenine quartiles (A) before and (B) after adjusting for potential confounders. The multivariable adjustment model includes sex, age, body mass index, smoking, exercise, steroid use within the past 6 months, and serum creatinine and albumin levels. The estimated means with 95% confidence intervals were generated and compared using analysis of covariance. Serum kynurenine quartiles: Q1=1.30–2.66 μM; Q2=2.67–3.35 μM; Q3=3.36–4.25 μM; Q4=4.26–9.42 μM. SMI, skeletal muscle mass index; SPPB, short physical performance battery. aStatistically significant difference from the lowest quartile (Q1).
Fig. 3. Plasma kynurenine pathway proteins and their associations with sarcopenia and related traits. (A) Schematic representation of the kynurenine biosynthesis pathway. Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) catalyze the conversion of tryptophan to kynurenine. (B) Comparison of plasma IDO1 and TDO2 levels between control and sarcopenia groups following 1:4 propensity score matching based on sex, age, body mass index (BMI), and genetic principal components (PCs). Matching was constrained to individuals of the same sex. Differences between the two groups were assessed using Student’s t tests. (C, D) Partial regression plots showing the association of plasma IDO1 (C) and TDO2 (D) levels with appendicular skeletal muscle mass (ASM) and grip strength in the matched population. Residuals from linear models adjusted for sex, age, BMI, and PCs are plotted on both axes. P values indicate the significance of the adjusted protein effect, and β coefficients represent the estimated effect size from the multiple linear regression. NS, not significant. aStatistically significant difference compared to the non-sarcopenia group.
Graphical abstract
Fig. 1.
Fig. 2.
Fig. 3.
Graphical abstract
Higher Circulating Kynurenine Levels Linked to Higher Risk of Sarcopenia in Older Adults: A Cohort Study and UK Biobank Analysis
| Characteristic | No sarcopenia (n=123) | Sarcopenia (n=42) | P value |
|---|---|---|---|
| Female sex | 102 (82.9) | 31 (73.8) | 0.257 |
| Age, yr | 75.2±5.2 | 79.7±4.8 | <0.001 |
| Body weight, kg | 59.6±9.5 | 53.5±5.6 | <0.001 |
| Height, cm | 154.9±6.5 | 153.0±6.8 | 0.113 |
| Body mass index, kg/m2 | 25.4±5.4 | 22.9±2.5 | 0.004 |
| Serum albumin, g/dL | 3.95±0.24 | 3.85±0.27 | 0.027 |
| Serum creatinine, mg/dL | 0.86±0.33 | 0.83±0.21 | 0.631 |
| Smoking | 19 (15.4) | 5 (11.9) | 0.510 |
| Regular exercise | 18 (14.6) | 3 (7.1) | 0.173 |
| Diabetes mellitus | 48 (39.0) | 14 (33.3) | 0.582 |
| Polypharmacy | 63 (51.2) | 26 (61.9) | 0.283 |
| Steroid use within the past 6 months | 4 (3.3) | 3 (7.1) | 0.372 |
| Fall in previous year | 22 (17.9) | 8 (19.0) | 0.821 |
| Appendicular skeletal muscle mass, kg | 15.2±2.9 | 13.1±2.2 | <0.001 |
| Skeletal muscle mass index, kg/m2 | 6.31±0.79 | 5.55±0.52 | <0.001 |
| Grip strength, kg | 25.9±6.2 | 19.8±5.0 | <0.001 |
| Usual gait speed, m/sec | 1.04±0.23 | 0.78±0.26 | <0.001 |
| Chair stand test time, sec | 10.5±5.4 | 17.0±13.2 | 0.003 |
| SPPB total score (ranges, 0–12) | 10.9±1.6 | 8.3±3.1 | <0.001 |
| Sarcopenia phenotype score (range, 0–3) | 0.72±0.56 | 2.38±0.49 | <0.001 |
| Variable | Serum kynurenine level |
Serum tryptophan level |
Serum KTR |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| β | SE | β | P value | β | SE | β | P value | β | SE | β | P value | |
| Unadjusted | ||||||||||||
| Skeletal muscle index | –0.181 |
0.045 |
–0.302 |
<0.001 |
0.004 | 0.003 | 0.100 | 0.201 | –13.6 |
3.280 |
–0.310 |
<0.001 |
| Grip strength | –1.298 |
0.369 |
–0.265 |
0.001 |
0.031 | 0.022 | 0.106 | 0.174 | –103.9 |
26.9 |
–0.290 |
<0.001 |
| Chair stand | 1.222 |
0.497 |
0.190 |
0.015 |
–0.060 |
0.030 |
–0.157 |
0.045 |
112.5 |
36.1 |
0.238 |
0.002 |
| Gait speed | –0.022 | 0.016 | –0.108 | 0.169 | 0.001 | 0.001 | 0.120 | 0.127 | –2.289 |
1.139 |
–0.156 |
0.046 |
| SPPB total score | –0.295 |
0.131 |
–0.174 |
0.026 |
0.013 | 0.008 | 0.133 | 0.090 | –25.1 |
9.574 |
–0.202 |
0.010 |
| SPS | 0.200 |
0.051 | 0.294 |
<0.001 |
–0.002 | 0.003 | –0.058 | 0.457 | 12.6 |
3.796 |
0.253 |
0.001 |
| Multivariable-adjusted | ||||||||||||
| Skeletal muscle index | –0.112 |
0.033 |
–0.186 |
0.001 |
0.002 | 0.002 | 0.046 | 0.423 | –8.920 |
2.489 |
–0.203 |
<0.001 |
| Grip strength | –0.704 |
0.305 |
–0.144 |
0.022 |
0.010 | 0.018 | 0.035 | 0.578 | –58.0 |
22.9 |
–0.162 |
0.012 |
| Chair stand | 0.724 | 0.481 | 0.112 | 0.134 | –0.052 | 0.029 | –0.137 | 0.069 | 87.3 |
35.9 |
0.185 |
0.016 |
| Gait speed | –0.011 | 0.015 | –0.056 | 0.461 | 0.001 | 0.001 | 0.114 | 0.135 | –1.644 | 1.130 | –0.112 | 0.148 |
| SPPB total score | –0.194 | 0.126 | –0.114 | 0.127 | 0.012 | 0.008 | 0.124 | 0.101 | –19.7 |
9.483 |
–0.158 |
0.040 |
| SPS | 0.153 |
0.049 |
0.225 |
0.002 |
–0.002 | 0.003 | –0.046 | 0.536 | 10.2 |
3.707 |
0.205 |
0.006 |
| Variable | OR (95% CI) per serum kynurenine SD increment | P value | OR (95% CI) per serum tryptophan SD increment | P value | OR (95% CI) per serum KTR SD increment | P value |
|---|---|---|---|---|---|---|
| Unadjusted | ||||||
| Sarcopenia | 2.10 (1.43–3.07) |
<0.001 |
0.98 (0.69–1.39) | 0.906 | 1.66 (1.17–2.35) |
0.005 |
| Low muscle mass | 2.09 (1.44–3.05) |
<0.001 |
1.03 (0.75–1.40) | 0.871 | 1.74 (1.21–2.51) |
0.003 |
| Weak muscle strength | 1.62 (1.12–2.36) |
0.011 |
1.12 (0.75–1.67) | 0.574 | 1.32 (0.92–1.89) | 0.127 |
| Poor physical performance | 1.12 (0.82–1.53) | 0.469 | 0.74 (0.53–1.02) | 0.065 | 1.28 (0.92–1.79) | 0.143 |
| Multivariable-adjusted | ||||||
| Sarcopenia | 2.31 (1.45–3.71) |
<0.001 |
1.01 (0.65–1.58) | 0.954 | 1.78 (1.15–2.75) |
0.010 |
| Low muscle mass | 2.97 (1.68–5.22) |
<0.001 |
1.12 (0.75–1.66) | 0.576 | 2.21 (1.27–3.86) |
0.005 |
| Weak muscle strength | 1.80 (1.15–2.81) |
0.010 |
1.14 (0.70–1.84) | 0.595 | 1.45 (0.95–2.24) | 0.087 |
| Poor physical performance | 0.97 (0.69–1.37) | 0.872 | 0.75 (0.53–1.08) | 0.121 | 1.12 (0.79–1.61) | 0.522 |
| Exposure | Outcome | MR method | nSNPs | Beta | SE | P value | MR-PRESSO global test P value |
|---|---|---|---|---|---|---|---|
| Plasma IDO1 level | Sarcopenia prevalence | Inverse-variance weighted | 125 | 0.105 |
0.040 |
0.010 |
0.92 |
Table 1. Basic Clinical Characteristics of the Study Participants
Values are expressed as number (%) or mean±standard deviation. Differences between the two groups were assessed using Student’s SPPB, short physical performance battery. Statistically significant values.
Table 2. Linear Regression Analysis to Determine the Association of Serum Kynurenine and Tryptophan Levels and Their Ratio with Muscle-Related Parameters
The Enter method was applied to this model. The multivariable adjustment model includes sex, age, body mass index, smoking, exercise, steroid use within the past 6 months, and serum creatinine and albumin levels. KTR, kynurenine/tryptophan ratio; β, unstandardized regression coefficient; SE, standard error; Statistically significant values.
Table 3. Logistic Regression Analyses to Determine the Odds Ratios for Sarcopenia and the Related Parameters according to the Increase in Serum Kynurenine and Tryptophan Levels and Their Ratio
The multivariable adjustment model includes sex, age, body mass index, smoking, exercise, steroid use within the past 6 months, and serum creatinine and albumin levels. OR, odds ratio; CI, confidence interval; SD, standard deviation; KTR, kynurenine/tryptophan ratio. Statistically significant values.
Table 4. Mendelian Randomization Analysis of the Causal Effect of Plasma IDO1 Protein Levels on Sarcopenia Risk Using UK Biobank GWAS Data
MR was performed to assess the causal relationship between plasma IDO1 protein levels and sarcopenia prevalence using summary statistics from an inhouse GWAS of the UK Biobank. Only cis-acting genetic variants (cis-SNPs) were used as instrumental variables. The MR-PRESSO global test was applied to assess horizontal pleiotropy. IDO1, indoleamine 2,3-dioxygenase 1; GWAS, genome-wide association study; MR, Mendelian randomization; nSNP, number of single nucleotide polymorphism; SE, standard error; MR-PRESSO, Mendelian Randomization Pleiotropy RESidual Sum and Outlier. Statistically significant values.
