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Physiological hypoxia restrains the senescence-associated secretory phenotype via AMPK-mediated mTOR suppression

Physiological hypoxia restrains the senescence-associated secretory phenotype via AMPK-mediated mTOR suppression

Authors :
Michela Borghesan
Boshi Wang
Konstantinos Evangelou
Thijmen van Vliet
Rossana Franzin
Simone Brandenburg
Marco Demaria
Marta Varela-Eirin
Marc A. Seelen
Vassilis G. Gorgoulis
Groningen Kidney Center (GKC)
Groningen Institute for Organ Transplantation (GIOT)
Damage and Repair in Cancer Development and Cancer Treatment (DARE)
Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
Source :
Molecular Cell, 81(9), 2041-+. CELL PRESS
Publication Year :
2021
Publisher :
Elsevier BV, 2021.

Abstract

Cellular senescence is a state of stable proliferative arrest triggered by damaging signals. Senescent cells persist during aging and promote age-related pathologies via the pro-inflammatory senescence-associated secretory phenotype (SASP), whose regulation depends on environmental factors. In vivo, a major environmental variable is oxygenation, which varies among and within tissues. Here, we demonstrate that senescent cells express lower levels of detrimental pro-inflammatory SASP factors in physiologically hypoxic environments, as measured in culture and in tissues. Mechanistically, exposure of senescent cells to low-oxygen conditions leads to AMPK activation and AMPK-mediated suppression of the mTOR-NF-kappa B signaling loop. Finally, we demonstrate that treatment with hypoxia-mimetic compounds reduces SASP in cells and tissues and improves strength in chemotherapy-treated and aged mice. Our findings highlight the importance of oxygen as a determinant for pro-inflammatory SASP expression and offer a potential new strategy to reduce detrimental paracrine effects of senescent cells.

Details

ISSN :
10972765
Volume :
81
Database :
OpenAIRE
Journal :
Molecular Cell
Accession number :
edsair.doi.dedup.....e41d049af8f7f1553a9fa42c40e99899
Full Text :
https://doi.org/10.1016/j.molcel.2021.03.018