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A BDNF-TrkB autocrine loop enhances senescent cell viability

Author

Listed:
  • Carlos Anerillas

    (National Institutes of Health)

  • Allison B. Herman

    (National Institutes of Health)

  • Rachel Munk

    (National Institutes of Health)

  • Amanda Garrido

    (National Institutes of Health)

  • Kwan-Wood Gabriel Lam

    (National Institutes of Health)

  • Matthew J. Payea

    (National Institutes of Health)

  • Martina Rossi

    (National Institutes of Health)

  • Dimitrios Tsitsipatis

    (National Institutes of Health)

  • Jennifer L. Martindale

    (National Institutes of Health)

  • Yulan Piao

    (National Institutes of Health)

  • Krystyna Mazan-Mamczarz

    (National Institutes of Health)

  • Jinshui Fan

    (National Institutes of Health)

  • Chang-Yi Cui

    (National Institutes of Health)

  • Supriyo De

    (National Institutes of Health)

  • Kotb Abdelmohsen

    (National Institutes of Health)

  • Rafael Cabo

    (National Institutes of Health)

  • Myriam Gorospe

    (National Institutes of Health)

Abstract

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.

Suggested Citation

  • Carlos Anerillas & Allison B. Herman & Rachel Munk & Amanda Garrido & Kwan-Wood Gabriel Lam & Matthew J. Payea & Martina Rossi & Dimitrios Tsitsipatis & Jennifer L. Martindale & Yulan Piao & Krystyna , 2022. "A BDNF-TrkB autocrine loop enhances senescent cell viability," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33709-8
    DOI: 10.1038/s41467-022-33709-8
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