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

Thijmen van Vliet, Marta Varela-Eirin, Boshi Wang, Michela Borghesan, Simone M Brandenburg, Rossana Franzin, Konstantinos Evangelou, Marc Seelen, Vassilis Gorgoulis, Marco Demaria*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

57 Citations (Scopus)
196 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)2041-+
Number of pages18
JournalMolecular Cell
Volume81
Issue number9
Early online date5-Apr-2021
DOIs
Publication statusPublished - 6-May-2021

Keywords

  • CELLULAR SENESCENCE
  • PARTIAL-PRESSURE
  • OXYGEN
  • GROWTH
  • CELLS
  • RESTRICTION
  • ACTIVATION
  • EXPRESSION
  • DAMAGE
  • DIET

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