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

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 beta-galactosidase (SA-beta-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-beta-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.

Automated summary

This study reveals that the absence of aryl hydrocarbon receptor (AhR) in aging mice exacerbates cellular senescence and liver progenitor cell proliferation, leading to an increased risk of hepatocarcinoma. AhR plays a role in the regulation of senescence by repressing the expression of senescence-associated genes. Depletion of senescent cells or restoration of AhR levels can reverse the senescence phenotype. These findings highlight the importance of AhR in modulating age-induced senescence and its potential role in liver tumorigenesis.