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.

Gut microbially produced tryptophan metabolite melatonin ameliorates osteoporosis via modulating SCFA and TMAO metabolism

“…24,72 Gut microbiota-associated tryptophan metabolism has emerged as one of the most extensively studied classes of metabolites involved in host-microbiota interactions, which has been proved to be associated with OP progression. 77 Here, we found that gut microbiota-derived tryptophan metabolite MLT was significantly decreased during OP advancement and negatively correlated with bone mass loss, which may be the key tryptophan metabolite closely linked to OP progression. MLT exhibits wide anti-inflammatory and antioxidation properties as well as protective effects on multiple organs such as the brain, angiocarpy, and liver.…”

Relationship of Low Vitamin B6 Status with Sarcopenia, Frailty, and Mortality: A Narrative Review

“…Recent evidence suggests that several elements of the kynurenine (a tryptophan metabolite) pathway have impacts on the formation, metabolism, and function of muscle and bone [ 75 ]. Some pathway elements, including kynurenine, kynurenic acid, quinolinic acid, and tryptophan metabolites, have been associated with positive or deleterious effects on muscle formation and function, involving the pathogenesis of sarcopenia and frailty.…”

The role of the kynurenine pathway in cardiovascular disease

“…Inflammatory factors induce the upregulation of IDO1 expression, resulting in the accumulation of KYN and its downstream metabolites, thereby triggering certain inflammatory diseases and muscle wasting syndromes. Additionally, KYN can mediate the inhibition of osteogenic gene expression through AhR, thereby inducing osteoporosis in the elderly (14). KYN is acknowledged as a neuroprotective agent with the ability to traverse the blood-brain barrier and directly exert neuroprotective effects within the brain (15).…”