ICSA2020 #icsa2020osaka

http://www.icsa2020-osaka.jp

**Postponed**

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Please save the new dates:

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December 12-15, 2021

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Members Featured Articles

Physiological hypoxia restrains the senescence-associated secretory phenotype via AMPK-mediated mTOR suppression

Thijmenvan Vliet, Marta Varela-Eirin, Boshi Wang, Michela Borghesan, Simone M.Brandenburg, Rossana Franzin, Konstantinos Evangelou, Marc Seelen, Vassilis Gorgoulis, Marco Demaria

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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..

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Paper of the Month

Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy

Xia Lium, Celine L. Hartman, Lingyun Li, Carolyn J. Albert, Fusheng Si, Aiqin Gao, Lan Huang, Yangjing Zhao, Wenli Lin, Eddy C. Hsueh, Lizong Shen, Qixiang Shao, Daniel F. Hoft, David A. Ford, Guangyong Peng

The functional state of T cells is a key determinant for effective antitumor immunity and immunotherapy. Cellular metabolism, including lipid metabolism, controls T cell differentiation, survival, and effector functions. Here, we report that development of T cell senescence driven by both malignant tumor cells and regulatory T cells is a general feature in cancers. Senescent T cells have active glucose metabolism but exhibit unbalanced lipid metabolism. This unbalanced lipid metabolism results in changes of expression of lipid metabolic enzymes, which, in turn, alters lipid species and accumulation of lipid droplets in T cells. Tumor cells and Treg cells drove elevated expression of group IVA phospholipase A2, which, in turn, was responsible for the altered lipid metabolism and senescence induction observed in T cells. Mitogen-activated protein kinase signaling and signal transducer and activator of transcription signaling coordinately control lipid metabolism and group IVA phospholipase A2 activity in responder T cells during T cell senescence. Inhibition of group IVA phospholipase A2 reprogrammed effector T cell lipid metabolism, prevented T cell senescence in vitro, and enhanced antitumor immunity and immunotherapy efficacy in mouse models of melanoma and breast cancer in vivo. Together, these findings identify mechanistic links between T cell senescence and regulation of lipid metabolism in the tumor microenvironment and provide a new target for tumor immunotherapy.

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