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 () had exacerbated cellular senescence and more liver progenitor cells. Senescence-associated markers β-galactosidase (SA-β-Gal), p16 and p21 and genes encoding senescence-associated secretory phenotype (SASP) factors TNF and IL1 were overexpressed in aged livers. Chromatin immunoprecipitation showed that AhR binding to those gene promoters repressed their expression, thus adjusting physiological levels in 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 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 and p21. Notably, depletion of senescent cells with the senolytic agent navitoclax restored expression of senescent markers in fibroblasts, whereas senescence induction by palbociclib induced an AhR-null-like phenotype in fibroblasts. AhR levels were downregulated by senescence in mouse lungs but restored upon depletion of p16-expressing senescent cells. Thus, AhR restricts age-induced senescence associated to a differentiated phenotype eventually inducing resistance to liver tumorigenesis.