Lack of the aryl hydrocarbon receptor accelerates aging in mice

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand‐activated transcription factor, largely known for its role in xenobiotic metabolism and detoxification as well as its crucial role as a regulator of inflammation. Here, we have compared a cohort wild‐type and AhR‐null mice along aging to study the relationship between this receptor and age‐associated inflammation, termed as “inflammaging,” both at a systemic and the CNS level. Our results show that AhR deficiency is associated with a premature aged phenotype, characterized by early inflammaging, as shown by an increase in plasma cytokines levels. The absence of AhR also promotes the appearance of brain aging anatomic features, such as the loss of the white matter integrity. In addition, AhR–/– mice present an earlier spatial memory impairment and an enhanced astrogliosis in the hippocampus when compared with their age‐matched AhR+/+ controls. Importantly, we have found that AhR protein levels decrease with age in this brain structure, strongly suggesting a link between AhR and aging.—Bravo‐Ferrer, I., Cuartero, M. I., Medina, V., Ahedo‐Quero, D., Peña‐Martínez, C., Pérez‐Ruíz, A., Fernández‐Valle, M. E., Hernández‐Sánchez, C., Fernández‐Salguero, P. M., Lizasoain, I., Moro, M. A. Lack of the aryl hydrocarbon receptor accelerates aging in mice. FASEB J. 33, 12644–12654 (2019). http://www.fasebj.org

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

“…It is discussed that AhR activation induces oxidative stress as a result of excessive generation of ROS. Recent studies indicate that AhR also affects several age-associated processes, such as vascular function or cellular senescence and age-associated macular degeneration (Hu et al, 2013;Singh et al, 2014;Eckers et al, 2016;Bravo-Ferrer et al, 2019). The recently generated AhR 3/ 3 mice showed a premature aging phenotype resulting in a reduced life span.…”

“…The recently generated AhR 3/ 3 mice showed a premature aging phenotype resulting in a reduced life span. Those mice display functionality decline in several organs (Fernandez-Salguero et al, 1995;Bravo-Ferrer et al, 2019). In contrast, the AhR 2/ 2 mice show a similar survival rate as wild type mice until 15 months of age and do not display a premature aging phenotype (Singh et al, 2014).…”

Identification of endogenous 1‐aminopyrene as a novel mediator of progressive chronic kidney disease via aryl hydrocarbon receptor activation

“…Another study showed that the treatment of mice with three Lactobacillus strains could metabolize tryptophan and alleviate intestinal inflammation through aryl hydrocarbon receptor activation, as the effects were abolished by an aryl hydrocarbon receptor antagonist (Lamas et al, 2016). In addition, aryl hydrocarbon receptor −/− mice showed earlier spatial memory impairment and enhanced astrogliosis in the hippocampus when compared to age-matched aryl hydrocarbon receptor +/+ controls, suggesting a link between aryl hydrocarbon receptor and aging (Bravo-Ferrer et al, 2019). Collectively, the current work and that of others suggested that aryl hydrocarbon receptor could be activated by aryl-containing metabolite during chronic kidney disease progression.…”

Indole-3-carbinol regulates microglia homeostasis and protects the retina from degeneration

“…Inactive AhR localizes in the cytoplasm and upon binding of a ligand, the protein dissociates from chaperones and translocates into the nucleus where it binds to nuclear response element and changes gene transcription required for cellular homeostasis [ 6 ]. AhR deficiency accelerates aging in mice and triggers inflammation [ 7 – 9 ], and AhR ligands play an important role in immune modulation [ 9 , 10 ].…”