The Aryl Hydrocarbon Receptor (AhR) in the Aging Process: Another Puzzling Role for This Highly Conserved Transcription Factor

Abstract

Aging is the most important risk factor for the development of major life-threatening diseases such as cardiovascular disorders, cancer, and neurodegenerative disorders. The aging process is characterized by the accumulation of damage to intracellular macromolecules and it is concurrently shaped by genetic, environmental and nutritional factors. These factors influence the functionality of mitochondria, which play a central role in the aging process. Mitochondrial dysfunction is one of the hallmarks of aging and is associated with increased fluxes of ROS leading to damage of mitochondrial components, impaired metabolism of fatty acids, dysregulated glucose metabolism, and damage of adjacent organelles. Interestingly, many of the environmental (e.g., pollutants and other toxicants) and nutritional (e.g., flavonoids, carotenoids) factors influencing aging and mitochondrial function also directly or indirectly affect the activity of a highly conserved transcription factor, the Aryl hydrocarbon Receptor (AhR). Therefore, it is not surprising that many studies have already indicated a role of this versatile transcription factor in the aging process. We also recently found that the AhR promotes aging phenotypes across species. In this manuscript, we systematically review the existing literature on the contradictory studies indicating either pro-or anti-aging effects of the AhR and try to reconcile the seemingly conflicting data considering a possible dependency on the animal model, tissue, as well as level of AhR expression and activation. Moreover, given the crucial role of mitochondria in the aging process, we summarize the growing body of evidence pointing toward the influence of AhR on mitochondria, which can be of potential relevance for aging.

Dietary and environmental factors have opposite AhR-dependent effects on C. elegans healthspan

“…Since its discovery, the variety of pathophysiological processes regulated by the AhR has rapidly grown and range from cell death, to immune response and neuronal development [ 6 ]. Contradictory studies also indicated a role for AhR in the aging process (reviewed in [ 7 ]) and more recently, pro-aging functions of AhR [ 8 , 9 ] have been described in an evolutionarily conserved manner from C. elegans to mammals. In mammals, in basal conditions, AhR is bound to heat shock protein 90 (HSP90), AhR interacting protein (AIP), and p23, which retain it in the cytoplasm, in a ligand-affine state.…”

Ahr-bacterial diet interaction modulates aging and associated pathologies inC. elegans

“…curcumin, UVB and BaP). The differential effects on lifespan and gene expression we observed upon ahr-1 genetic-or RNAi-mediated suppression interestingly reveal the importance of fine-tuning its activity in a dose and/or tissue-dependent manner, which very nicely recapitulate the variety of phenotypic features described in mammals upon dosage effects or tissue-specific depletion (Brinkmann et al, 2020). Moreover, to our surprise, we found that besides increased resistance to heat-shock, lack of ahr-1 did not confer resistance to any other investigated insult, such as metabolic stress or radiation, and in fact sensitize animals to UVB.…”

“…Since its discovery, the variety of pathophysiological processes regulated by the AhR has grown and range from cell death, to immune response and neuronal development (Esser, Lawrence et al, 2018). Contradictory studies also indicated a role for AhR in the aging process (reviewed in (Brinkmann, Ale-Agha et al, 2020)) and more recently, pro-aging functions of AhR (Eckers, Jakob et al, 2016, Williams, Mouchiroud et al, 2014 have been described in an evolutionarily conserved manner from C. elegans to mammals. In mammals, in basal conditions, AhR is bound by HSP90, AIP, and p23, which retain it in the cytoplasm, in a ligand-affine state.…”

Aryl Hydrocarbon Receptor Role in Co-Ordinating SARS-CoV-2 Entry and Symptomatology: Linking Cytotoxicity Changes in COVID-19 and Cancers; Modulation by Racial Discrimination Stress

“…These authors also found the AhR to be increased in the serum of Alzheimer’s disease patients. Many studies have shown the AhR to be relevant to the ageing process, promoting an ageing phenotype across different species, which the authors propose to be mediated via effects on mitochondrial function [ 173 ]. The levels of AhR over age in different organs and tissues, and especially in immune cells, will be important to determine, including in correlation with SARS-CoV-2 infection severity.…”