Aryl hydrocarbon receptor blocks aging-induced senescence in the liver and fibroblast cells

Abstract

Aging impairs organismal homeostasis leading to multiple pathologies. Yet, the mechanisms and molecular intermediates involved are largely unknown. Here, we report that aged aryl hydrocarbon receptor-null mice ( AhR−/− ) had exacerbated cellular senescence and more liver progenitor cells. Senescence-associated markers β-galactosidase (SA-β-Gal), p16 Ink4a and p21 Cip1 and genes encoding senescence-associated secretory phenotype (SASP) factors TNF and IL1 were overexpressed in aged AhR−/− livers. Chromatin immunoprecipitation showed that AhR binding to those gene promoters repressed their expression, thus adjusting physiological levels in AhR+/+ livers. MCP-2, MMP12 and FGF secreted by senescent cells were overproduced in aged AhR-null livers. Supporting the relationship between senescence and stemness, liver progenitor cells were overrepresented in AhR−/− mice, probably contributing to increased hepatocarcinoma burden. These AhR roles are not liver-specific since adult and embryonic AhR-null fibroblasts underwent senescence in culture, overexpressing SA-β-Gal, p16 Ink4a and p21 Cip1 . Notably, depletion of senescent cells with the senolytic agent navitoclax restored expression of senescent markers in AhR−/− fibroblasts, whereas senescence induction by palbociclib induced an AhR-null-like phenotype in AhR+/+ fibroblasts. AhR levels were downregulated by senescence in mouse lungs but restored upon depletion of p16 Ink4a -expressing senescent cells. Thus, AhR restricts age-induced senescence associated to a differentiated phenotype eventually inducing resistance to liver tumorigenesis.

Aryl hydrocarbon receptor (AhR) reveals evidence of antagonistic pleiotropy in the regulation of the aging process

“…All these alterations are consistent with the theory of antagonistic pleiotropy. Surprisingly, recent studies have revealed that lack of AhR factor is associated with premature aging process characterized by enhanced cellular senescence and increased serum levels of both pro-inflammatory and anti-inflammatory cytokines, such as IL-6, TNF-α, and IL-10 [ 225 , 226 ]. Nacarino-Palma et al [ 226 ] reported that AhR depletion significantly increased tumor incidence in mouse liver with aging.…”

“…Surprisingly, recent studies have revealed that lack of AhR factor is associated with premature aging process characterized by enhanced cellular senescence and increased serum levels of both pro-inflammatory and anti-inflammatory cytokines, such as IL-6, TNF-α, and IL-10 [ 225 , 226 ]. Nacarino-Palma et al [ 226 ] reported that AhR depletion significantly increased tumor incidence in mouse liver with aging. Moreover, they demonstrated that the deficiency of AhR factor robustly expanded the number of senescent cells in the liver preceding the aging process.…”

“…An increased cellular senescence was not only a liver-specific process since AhR-deficient embryonic and adult fibroblasts displayed increased cellular senescence in vitro cell cultures. These results indicate that lack of AhR factor accelerates premature aging process and tumorigenesis, robustly present already at the age of 12–15 months [ 225 , 226 ]. Given that AhR signaling promotes cellular senescence with aging (see above), these observations on premature aging process in the AhR-null mice seem to be contradictory to the antagonistic pleiotropy theory (Fig.…”

From Nucleus to Organs: Insights of Aryl Hydrocarbon Receptor Molecular Mechanisms

“…This absence of AHR increases the susceptibility to hepatocarcinoma development after diethylnitrosamine (DEN) treatment, but also leading to a higher regenerative capacity [ 132 , 133 ]. Therefore, AHR has a direct implication on both processes, since its absence exacerbates cellular senescence markers and increases liver progenitor cells in age-induced hepatocarcinoma [ 99 ]. Furthermore, its exogenous modulation by TCDD inhibits hepatic regeneration in mice after partial hepatectomy of the liver [ 134 , 135 ], while hexachlorobenzene (HCB) induces its expression in preneoplastic foci both on rat liver and HepG2 human hepatocarcinoma cell line [ 136 ].…”

Insomnia in Forensic Detainees: Is Salience Network the Common Pathway for Sleep, Neuropsychiatric, and Neurodegenerative Disorders?

“…At the molecular level, incarceration, insomnia, and severe mental illness have been associated with premature cellular senescence, a phenotype marked by increased intracellular iron and mitochondrial damage [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Premature cellular senescence is driven by the aryl hydrocarbon receptor (AhR), expressed in neuronal cytosol and mitochondria [ 19 , 20 , 21 ]. Senescent cells upregulate intracellular iron which, in the proximity of cytosolic fats, increases the risk of lipid peroxidation and neuronal demise by ferroptosis [ 22 , 23 , 24 ].…”