Ongoing Clinical Trials in Aging-Related Tissue Fibrosis and New Findings Related to AhR Pathways

Abstract

Fibrosis is a pathological manifestation of wound healing that replaces dead/damaged tissue with collagen-rich scar tissue to maintain homeostasis, and complications from fibrosis contribute to nearly half of all deaths in the industrialized world. Ageing is closely associated with a progressive decline in organ function, and the prevalence of tissue fibrosis dramatically increases with age. Despite the heavy clinical and economic burden of organ fibrosis as the population ages, to date, there is a paucity of therapeutic strategies that are specifically designed to slow fibrosis. Aryl hydrocarbon receptor (AhR) is an environment-sensing transcription factor that exacerbates aging phenotypes in different tissues that has been brought back into the spotlight again with economic development since AhR could interact with persistent organic pollutants derived from incomplete waste combustion. In addition, gut microbiota dysbiosis plays a pivotal role in the pathogenesis of numerous diseases, and microbiota-associated tryptophan metabolites are dedicated contributors to fibrogenesis by acting as AhR ligands. Therefore, a better understanding of the effects of tryptophan metabolites on fibrosis modulation through AhR may facilitate the exploitation of new therapeutic avenues for patients with organ fibrosis. In this review, we primarily focus on how tryptophan-derived metabolites are involved in renal fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis and cardiac fibrosis. Moreover, a series of ongoing clinical trials are highlighted.

Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases

“…Tryptophan is an essential amino acid obtained through dietary sources and acts as a biosynthetic precursor to several microbial and host metabolites, including indole. 425,651 Notably, metagenomic analysis of PD gut microbiome has revealed a reduction in the tryptophan biosynthesis pathway. 331 Several indole derivatives, including indole-3-ethanol, indole-3-pyruvate, and indole-3aldehyde, maintain the integrity of the apical junctional complex and improve intestinal barrier integrity by activating the epithelial AHR (Fig.…”

Aryl hydrocarbon receptor: Linking environment to aging process in elderly patients with asthma

“…[ 4 ] Aryl hydrocarbon receptor (AhR) is a cytoplasmic receptor and mainly expressed at barrier surfaces, including the skin, respiratory tract, and gastrointestinal tract, linking environmental, microbial, and metabolic cues to biological and pathophysiological changes through regulating complex transcriptional programs. [ 5 6 7 8 ] In recent years, mounting evidence has revealed that AhR plays an important role in regulating environmental factor-triggered age-associated phenotypes. The human lung is one of the important organs highly impacted by aging and has the largest surface area exposed to environmental pollutants and biological, immunological, and xenobiotic stress.…”

TGF-β as A Master Regulator of Aging-Associated Tissue Fibrosis

“…The burden of fibrosis is significant, and twenty-five percent of the world's population is affected [ 3 ]; the annualized incidence of major fibrosis-related conditions is approaching five percent [ 2 ]. Aging is closely related to the progressive decline in organ function [ 4 ]. The accumulation of senescent cells is a major feature of organismal aging [ 5 ].…”