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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
- 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.
- Subjects :
- AMP-Activated Protein Kinases
OXYGEN
ACTIVATION
0302 clinical medicine
Hydroxybenzoates
Hypoxia
DAMAGE
0303 health sciences
Antibiotics, Antineoplastic
TOR Serine-Threonine Kinases
CELLULAR SENESCENCE
Age Factors
NF-kappa B
Phenotype
Cell Hypoxia
Cell biology
PARTIAL-PRESSURE
GROWTH
Inflammation Mediators
medicine.symptom
RESTRICTION
Signal Transduction
EXPRESSION
Senescence
Glycine
Cellular senescence
Biology
DIET
03 medical and health sciences
Paracrine signalling
Cell Line, Tumor
Paracrine Communication
medicine
Animals
Humans
Muscle Strength
Molecular Biology
PI3K/AKT/mTOR pathway
Cell Proliferation
030304 developmental biology
Senescence-Associated Secretory Phenotype
fungi
AMPK
Cell Biology
Hypoxia (medical)
Isoquinolines
Mice, Inbred C57BL
Doxorubicin
CELLS
030217 neurology & neurosurgery
Subjects
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