The Aryl Hydrocarbon Receptor, Epigenetics and the Aging Process

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor, classically associated with the regulation of xenobiotic metabolism in response to environmental toxins. In recent years, transgenic rodent models have implicated AhR in aging and longevity. Moreover, several AhR ligands, such as resveratrol and quercetin, are compounds proven to extend the lifespan of model organisms. In this paper, we first review AhR biology with a focus on aging and highlight several AhR ligands with potential anti-aging properties. We outline how AhR-driven expression of xenobiotic metabolism genes into old age may be a key mechanism through which moderate induction of AhR elicits positive benefits on longevity and healthspan. Furthermore, via integration of publicly available datasets, we show that liver-specific AhR target genes are enriched among genes subject to epigenetic aging. Changes to epigenetic states can profoundly affect transcription factor binding and are a hallmark of the aging process. We suggest that the interplay between AhR and epigenetic aging should be the subject of future research and outline several key gaps in the current literature. Finally, we recommend that a broad range of non-toxic AhR ligands should be investigated for their potential to promote healthspan and longevity.

Keywords: AhR ligands; TCDD; Xenobiotic metabolism; quercetin; resveratrol.

Figure 1.. The role of the transcription factor AhR in drug metabolism

AhR serves as an intracellular mediator of the xenobiotic metabolic pathway as it regulates the transcription of several phase I and phase II drug-metabolizing enzymes (left panel). Upon ligand binding, AhR decouples from molecular chaperones and shuttles to the nucleus where it forms a heterodimer with ARNT, allowing it to bind to XREs to regulate gene transcription. Figure created with BioRender.com.

Figure 2.

(A) Binding motif of the xenobiotic responsive element (XRE1), (B) Binding motif of the xenobiotic responsive element (XRE2), (C) Bulk tissue gene expression of AHR obtained from: the GTEx Portal on 14/10/2022

Figure 3.. Summary of the AhR activation on the aging phenotype

The type and dose of AhR ligands have varying effects on aging phenotype; (a) potent AhR ligands like TCDD produce accelerated aging phenotype and toxic effects, (b) AhR ligands have beneficial anti-aging effects, (c) AhR knockout models lack the beneficial effects of ligands. Figure created with BioRender.com.