Τίτλος:
Physiological hypoxia restrains the senescence-associated secretory phenotype via AMPK-mediated mTOR suppression
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
van Vliet, T.
Varela-Eirin, M.
Wang, B.
Borghesan, M.
Brandenburg, S.M.
Franzin, R.
Evangelou, K.
Seelen, M.
Gorgoulis, V.
Demaria, M.
Περιοδικό:
Molecular Cell
Λέξεις-κλειδιά:
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
DOI:
10.1016/j.molcel.2021.03.018
