BDNF-TrkB Interaction as a Potential Target for Novel Senolytic Therapies
Researchers continue to investigate the fundamental biology of cellular senescence, and every so often they turn up new targets that might be the basis for development of novel senolytic therapies. First generation senolytic treatments, that provoke a sizable fraction of senescent cells in aged tissues into self-destruction, have produced impressive results in aged mice, extending life, but more importantly rapidly reversing many measures of aging and age-related disease. While many different forms of senolytic treatment are presently under preclinical and clinical development, there will always be room for more, given that every human much over the age of 50 is a potential repeat customer.
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.