The Role of the Kynurenine Pathway in the Pathophysiology of Frailty, Sarcopenia, and Osteoporosis

Abstract

Tryptophan is an essential nutrient required to generate vitamin B3 (niacin), which is mainly involved in energy metabolism and DNA production. Alterations in tryptophan metabolism could have significant effects on aging and musculoskeletal health. The kynurenine pathway, essential in tryptophan catabolism, is modulated by inflammatory factors that are increased in older persons, a process known as inflammaging. Osteoporosis, sarcopenia, osteosarcopenia, and frailty have also been linked with chronically increased levels of inflammatory factors. Due to the disruption of the kynurenine pathway by chronic inflammation and/or changes in the gut microbiota, serum levels of toxic metabolites are increased and are associated with the pathophysiology of those conditions. In contrast, anabolic products of this pathway, such as picolinic acid, have demonstrated a positive effect on skeletal muscle and bone. In addition, physical activity can modulate this pathway by promoting the secretion of anabolic kynurenines. According to the evidence collected, kynurenines could have a promising role as biomarkers for osteoporosis sarcopenia, osteosarcopenia, and frailty in older persons. In addition, some of these metabolites could become important targets for developing new pharmacological treatments for these conditions.

Keywords: aging; biomarkers; frailty; inflammation; kynurenine pathway; older adults; osteoporosis; osteosarcopenia; sarcopenia; tryptophan.

Figure 1

Critical steps of the kynurenine pathway of Trp degradation. Nicotinamide adenine dinucleotide (NAD+), the main end product of this pathway, is a coenzyme for redox reactions central to energy metabolism, which also influences many key cellular functions. Indoleamine 2,3-dioxygenase 1 (IDO1), one of the main enzymes of this pathway, catalyzes the extrahepatic production of kynurenine. Abbreviations: Tryptophan 2,3-dioxygenase (TDO); kynurenine aminotransferase 1-4 (KYAT 1-4); kynurenine 3-monooxygenase (KMO); Kynureninase (KYNU); Kynurenine 3-monooxygenase (KMO).

Figure 2

Due to inflammaging, interleukin (IL)-6, IL-1β, and interferon (IF)-γ levels are increased, inducing high levels of indoleamine 2,3-dioxygenase 1 (IDO1) activity. As a result, high kynurenine (KYN) concentrations are observed. This process could explain, in part, the pathogenesis of several tissue loss/inflammatory age-related diseases such as osteoporosis, sarcopenia, osteosarcopenia, and frailty. Trp: tryptophan (Trp).

Figure 3

The role of kynurenines in bone metabolism and the pathogenesis of osteoporosis. High levels of kynurenine (KYN), anthranilic acid(AA), and 3-hydroxykynurenine (3-HK) and low levels of quinolinic acid (QUIN), picolinic acid (PIC), 3-hydroxy anthranilic acid (3-HAA), and NAD+ have been associated with changes in bone metabolism and increased risk for osteoporosis and fractures. These changes involved low levels of osteoblast differentiation and function and high levels of marrow adipogenesis and bone resorption by the osteoclasts.

Figure 4

Sarcopenia has been linked with high levels of 3-HAA, QUIN, KYN, and QUIN/KYN ratios, as well as low levels of KYNA and KYNA/QUIN, KYNA/PIC, KYNA/KYN, and PIC/QUIN ratios. Low physical activity, a major risk factor for sarcopenia, can modulate the kynurenine pathway with less KYN conversion to KYNA due to low PPARα/δ. Aging can also affect the kynurenine pathway and induce sarcopenia via inflammaging. Abbreviations: Kynurenic acid (KYNA); Kynurenine (KYN); Quinolinic acid (QUIN); Picolinic acid (PIC); 3-hydroxy anthranilic acid (3-HAA).

Figure 5

Serum levels of kynurenines are altered in frail older persons. Abbreviations: Kynurenic acid (KYNA); Kynurenine (KYN); Quinolinic acid (QUIN); Picolinic acid (PIC); tryptophan (Trp).