Association Between Tryptophan Metabolites, Physical Performance, and Frailty in Older Persons

Abstract

Frailty is defined as a syndrome of physiological decline in late life, characterized by marked vulnerability to adverse health outcomes. A robust biomarker for frailty is still lacking. Tryptophan (TRP) metabolism through the kynurenine pathway (KP) plays essential roles in aging, the musculoskeletal system, and physical performance. In this study, we quantified 7 KP metabolites, including kynurenine (KYN), kynurenine acid (KYNA), quinolinic acid (QUIN), picolinic acid (PIC), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), and anthranilic acid (AA) using ultra-high-performance liquid chromatography and gas chromatography-mass spectrometry in the serum of 85 participants (median age 75; 65% female; 28 non-frail, 29 pre-frail, and 28 frail) at the Nepean Osteoporosis and Frailty (NOF) Study. We looked at the association between TRP metabolites and physical performance, sarcopenia, and frailty. After adjusting for age and sex, our results showed that KYN and KYN/TRP were associated with higher interleukin (IL)-6 levels (r = .324 and r = .390, respectively). KYNA and its ratios to other products (mainly KYNA/KYN, KYNA/QUIN, and KYNA/PIC) were associated with a lower likelihood of frailty by Fried's criteria (OR 0.93 [0.88, 0.98], P = .009) and Rockwood index (r = -.241, P = .028) as well as a lower likelihood of sarcopenia (OR 0.88 [0.78, 1.00], P = .049). QUIN and QUIN/KYN showed an association with increased IL-6 (r = .293 and .204 respectively), higher likelihood of frailty (OR 1.02 [1.00, 1.04], P = .029 and OR 6.43 [2.23, 18.51], P = .001 respectively) and lower physical function (r = -.205 and r = -.292). In conclusion, different TRP metabolites have various associations with physical performance, frailty, and sarcopenia. Defining the underlying mechanisms may permit the development and validation of new biomarkers and therapeutics for frailty and musculoskeletal conditions targeting specific metabolites of the TRP catabolic pathway.

Keywords: Tryptophan; frailty; kynurenine; osteosarcopenia; sarcopenia.

Figure 1.

The kynurenine pathway of tryptophan metabolism. Metabolism of tryptophan (TRP) results in the neurotransmitters serotonin and melatonin and, via the kynurenine pathway (KP), to nicotinamide adenine dinucleotide. Kynurenine (KYN) is the initial rate-limiting KP product of TRP metabolism by the enzymes indoleamine-2,3-dioxygenase (IDO-1) and tryptophan dioxygenase. KYN is then converted via kynurenine aminotransferases (KATI/II/III) into kynurenic acid (KYNA) and Anthranilic acid (AA). 3-hydroxykynurenine (3-HK) is produced by further metabolism of KYN to 3-Hydroxyanthranilic acid (3-HAA). Sequential conversion to 2-amino-3-carboxymuconate-semialdehyde is the penultimate step leading to the enzymatic production of picolinic acid (PIC) and the (non-enzymatic) production of quinolinic acid (QUIN). Further conversion of QUIN to the essential cofactor NAD+ is catalyzed by quinolinate phosphoribosyltransferase (QPRT).

Figure 2.

The biological effect of tryptophan metabolites on older persons.