TY - JOUR
TI - Physiological hypoxia restrains the senescence-associated secretory phenotype via AMPK-mediated mTOR suppression
AU - van Vliet, T.
AU - Varela-Eirin, M.
AU - Wang, B.
AU - Borghesan, M.
AU - Brandenburg, S.M.
AU - Franzin, R.
AU - Evangelou, K.
AU - Seelen, M.
AU - Gorgoulis, V.
AU - Demaria, M.
JO - Molecular Cell
PY - 2021
VL - 81
TODO - 9
SP - 2041-2052.e6
PB - Cell Press
SN - 1097-2765, 1097-4164
TODO - 10.1016/j.molcel.2021.03.018
TODO - biological factor;  CXCL1 chemokine;  doxorubicin;  gamma interferon inducible protein 10;  glucose transporter 1;  hydroxymethylglutaryl coenzyme A reductase kinase;  immunoglobulin enhancer binding protein;  interleukin 1alpha;  interleukin 1beta;  interleukin 6;  mammalian target of rapamycin;  monocyte chemotactic protein 1;  oxygen;  phosphoinositide dependent protein kinase 1;  podocin;  protein p16;  protein p21;  protein S6;  RANTES;  Ras protein;  roxadustat;  senescence associated secretory phenotype factor;  unclassified drug;  antineoplastic antibiotic;  autacoid;  doxorubicin;  FG-4592;  glycine;  hydroxybenzoic acid derivative;  hydroxymethylglutaryl coenzyme A reductase kinase;  immunoglobulin enhancer binding protein;  isoquinoline derivative;  MTOR protein, human;  mTOR protein, mouse;  protocatechuic acid;  target of rapamycin kinase, AMPK signaling;  animal cell;  animal experiment;  animal model;  animal tissue;  Article;  cell aging;  cell hypoxia;  chemotherapy;  controlled study;  DNA damage;  environmental factor;  grip strength;  immunohistochemistry;  in vivo study;  lung fibroblast;  male;  mouse;  mTOR signaling;  muscle strength;  muscle weakness;  nonhuman;  primary culture;  protein expression;  protein phosphorylation;  proximal tubule cell;  skin fibroblast;  tissue oxygenation;  age;  animal;  C57BL mouse;  cell hypoxia;  cell proliferation;  drug effect;  enzymology;  human;  hypoxia;  metabolism;  paracrine signaling;  pathology;  pathophysiology;  phenotype;  signal transduction;  tumor cell line, Age Factors;  AMP-Activated Protein Kinases;  Animals;  Antibiotics, Antineoplastic;  Cell Hypoxia;  Cell Line, Tumor;  Cell Proliferation;  Cellular Senescence;  Doxorubicin;  Glycine;  Humans;  Hydroxybenzoates;  Hypoxia;  Inflammation Mediators;  Isoquinolines;  Mice, Inbred C57BL;  Muscle Strength;  NF-kappa B;  Paracrine Communication;  Phenotype;  Signal Transduction;  TOR Serine-Threonine Kinases
TODO - 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. © 2021 Elsevier Inc.
ER -