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bioRxiv · 10.1101/2021.02.25.432074

ARYL HYDROCARBON RECEPTOR BLOCKS AGING-INDUCED SENESCENCE IN THE LIVER AND FIBROBLAST CELLS

Nacarino Palma, A.·Rico Leo, E. M.·Campisi, J.·Ramanathan, A.·Merino, J. M.·Fernandez-Salguero, P. M.
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Abstract

Aging induces progressive organ degeneration and worsening of tissue homeostasis leading to multiple pathologies. Yet, little is known about the mechanisms and molecular intermediates involved. Here, we report that aged aryl hydrocarbon receptor-null mice (AhR-/-) had exacerbated senescence and larger numbers of liver progenitor cells. Senescence-associated markers {beta}-galactosidase (SA-{beta}-Gal), p16Ink4a and p21Cip1 and genes of the senescence-associated secretory phenotype (SASP) TNF and IL1 were overexpressed in aged AhR-/- livers. AhR binding to the promoter of those genes, as shown by chromatin immunoprecipitation, likely had a repressive effect maintaining their physiological levels in AhR+/+ livers. Furthermore, factors secreted by senescent cells MCP-2, MMP12 and FGF were also produced at higher levels in aged AhR-null livers. Supporting the linkage between senescence and stemness, liver progenitor cells were more abundant in AhR-/- mice, which could probably contribute to their increased hepatocarcinoma burden. These roles of AhR are not liver-specific since adult and embryonic AhR-null fibroblasts acquired cellular senescence upon culturing with overexpression of SA-{beta}-Gal, p16Ink4a and p21Cip1. Notably, depletion of senescent cells with the senolytic agent navitoclax restored basal expression of senescent markers in AhR-/- fibroblasts. Oppositely, senescence promoter palbociclib induced an AhR-null like phenotype in AhR+/+ fibroblasts. Moreover, doxycycline-induced senescence reduced AhR levels while depletion of p16Ink4a-expressing senescent cells restored basal AhR levels in mouse lungs. Thus, AhR is needed to restrict age-induced senescence, and such activity seems to correlate with a more differentiated phenotype and with increased resistance to liver tumorigenesis.

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Nacarino Palma, A., Rico Leo, E. M., Campisi, J., Ramanathan, A., Merino, J. M., Fernandez-Salguero, P. M.. 2021-02-25. ARYL HYDROCARBON RECEPTOR BLOCKS AGING-INDUCED SENESCENCE IN THE LIVER AND FIBROBLAST CELLS. https://doi.org/10.1101/2021.02.25.432074

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