fg-4592 and protocatechuic-acid

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.

Topics: 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