| First Author | Nacarino-Palma A | Year | 2022 |
| Journal | Aging (Albany NY) | Volume | 14 |
| Issue | 10 | Pages | 4281-4304 |
| PubMed ID | 35619220 | Mgi Jnum | J:326605 |
| Mgi Id | MGI:7315107 | Doi | 10.18632/aging.204103 |
| Citation | Nacarino-Palma A, et al. (2022) Aryl hydrocarbon receptor blocks aging-induced senescence in the liver and fibroblast cells. Aging (Albany NY) 14(10):4281-4304 |
| abstractText | 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. |
