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. Epub 2021 Apr 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Age Factors
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Cellular Senescence* / drug effects
  • Doxorubicin / pharmacology
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Humans
  • Hydroxybenzoates / pharmacology
  • Hypoxia / enzymology*
  • Hypoxia / pathology
  • Hypoxia / physiopathology
  • Inflammation Mediators / metabolism
  • Isoquinolines / pharmacology
  • Mice, Inbred C57BL
  • Muscle Strength
  • NF-kappa B / metabolism
  • Paracrine Communication
  • Phenotype
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*


  • Antibiotics, Antineoplastic
  • Hydroxybenzoates
  • Inflammation Mediators
  • Isoquinolines
  • NF-kappa B
  • protocatechuic acid
  • Doxorubicin
  • MTOR protein, human
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Glycine
  • roxadustat