TY - JOUR
T1 - A BDNF-TrkB autocrine loop enhances senescent cell viability
AU - Anerillas, Carlos
AU - Herman, Allison B.
AU - Munk, Rachel
AU - Garrido, Amanda
AU - Lam, Kwan Wood Gabriel
AU - Payea, Matthew J.
AU - Rossi, Martina
AU - Tsitsipatis, Dimitrios
AU - Martindale, Jennifer L.
AU - Piao, Yulan
AU - Mazan-Mamczarz, Krystyna
AU - Fan, Jinshui
AU - Cui, Chang Yi
AU - De, Supriyo
AU - Abdelmohsen, Kotb
AU - de Cabo, Rafael
AU - Gorospe, Myriam
N1 - Funding Information:
This work was supported in its entirety by the National Institute on Aging Intramural Research Program of the National Institutes of Health. We thank S. Camandola (NIA) for help with the mouse experiments.
Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2022/12
Y1 - 2022/12
N2 - Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions aim at selectively eliminating senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors capable of triggering apoptosis of several senescent, but not proliferating, human cells. Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF signaling suggested an autocrine function for TrkB and BDNF, which activated ERK5 and elevated BCL2L2 levels, favoring senescent cell survival. Treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. We propose that the activation of TrkB by SASP factor BDNF promotes cell survival and could be exploited therapeutically to reduce the senescent-cell burden.
AB - Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions aim at selectively eliminating senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors capable of triggering apoptosis of several senescent, but not proliferating, human cells. Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF signaling suggested an autocrine function for TrkB and BDNF, which activated ERK5 and elevated BCL2L2 levels, favoring senescent cell survival. Treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. We propose that the activation of TrkB by SASP factor BDNF promotes cell survival and could be exploited therapeutically to reduce the senescent-cell burden.
UR - https://www.scopus.com/pages/publications/85140229738
UR - https://www.scopus.com/pages/publications/85140229738#tab=citedBy
U2 - 10.1038/s41467-022-33709-8
DO - 10.1038/s41467-022-33709-8
M3 - Article
C2 - 36266274
AN - SCOPUS:85140229738
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6228
ER -