Journal
MOLECULAR CELL
Volume 81, Issue 9, Pages 2041-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2021.03.018
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Funding
- Dutch Cancer Foundation (KWF)
- European Union [722729]
- National Public Investment Program of the Ministry of Development and Investment/General Secretariat for Research and Technology [2020SE01300001]
- Welfare Foundation for Social & Cultural Sciences (KIKPE), Greece
- Hellenic Foundation for Research and Innovation (HFRI) [775]
- National and Kapodistrian University of Athens (NKUA) Special Account for Research Grants (SARG) [70/3/9816, 70/3/12128, 70/3/15603]
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Cellular senescence is a stable proliferative arrest triggered by damaging signals, and senescent cells express lower levels of detrimental pro-inflammatory SASP factors in physiologically hypoxic environments. Exposure to low-oxygen conditions leads to AMPK activation and suppression of the mTOR-NF-kappa B signaling loop, reducing SASP expression in cells and tissues. Treatment with hypoxia-mimetic compounds can improve strength in chemotherapy-treated and aged mice by reducing detrimental paracrine effects of senescent cells.
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.
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