2. Academic Validation
  3. 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

  • Mol Cell. 2021 May 6;81(9):2041-2052.e6. doi: 10.1016/j.molcel.2021.03.018.
Thijmen van Vliet 1,  Marta Varela-Eirin 1,  Boshi Wang 1,  Michela Borghesan 1,  Simone M Brandenburg 1,  Rossana Franzin 2,  Konstantinos Evangelou 3,  Marc Seelen 2,  Vassilis Gorgoulis 4,  Marco Demaria 5
Affiliations

Affiliations

  • 1 European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, Groningen, 9713 AV, the Netherlands.
  • 2 Experimental Nephrology Department, University Medical Center Groningen, University of Groningen, Groningen, 9713 GZ, the Netherlands.
  • 3 Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens 157 72, Greece.
  • 4 Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens 157 72, Greece; Faculty Institute for Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9NQ, UK; Biomedical Research Foundation, Academy of Athens, Athens 115 27, Greece; Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens 157 72, Greece.
  • 5 European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, Groningen, 9713 AV, the Netherlands. Electronic address: [email protected].
PMID: 33823141 DOI: 10.1016/j.molcel.2021.03.018
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-κB 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.

Keywords

SASP; aging; hypoxia; hypoxia mimetics; oxygen; p16; senescence.

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