Breathe it in – Spotlight on senescence and regeneration in the lung

Majewska, Julia; Krizhanovsky, Valery

doi:10.1016/j.mad.2021.111550

Cited by 7 publications

(4 citation statements)

References 86 publications

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“…The finding that a neuronal survival paradigm is utilized by senescent cells to support viability was interesting, but it was not entirely unexpected, as activation of TrkB by BDNF (and more generally Trk receptors by neurotrophins) has been described outside of the nervous system, particularly in developmental and tissue repair processes in several organs 30,[41][42][43] . On the other hand, aberrant activation of the BDNF-TrkB axis has been described in age-related pathologies such as lung fibrosis, sarcopenia, cancer, and kidney disease [44][45][46][47][48] ; interestingly, all these processes causing age-associated declines and diseases have been linked to cellular senescence [49][50][51][52][53][54] . Thus, it will be important to determine if BDNF secreted by senescent cells contributes to these paradigms by influencing surrounding cells, and possibly by promoting an EMT-like program 46,55 .…”

Section: Discussionmentioning

confidence: 99%

A BDNF-TrkB autocrine loop enhances senescent cell viability

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 99%

A BDNF-TrkB autocrine loop enhances senescent cell viability

et al. 2022

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“…On the other hand, aberrant activation of the BDNF-TrkB axis has been described in age-related pathologies such as lung fibrosis, sarcopenia, cancer, and kidney disease [40][41][42][43][44] . Interestingly, all these processes, from the developmental responses to the age-associated declines and diseases, have been linked to cellular senescence [45][46][47][48][49][50] . Thus, it will be important to determine if BDNF contributes to these paradigms through its actions on TrkB-expressing senescent cells.…”

Section: Discussionmentioning

confidence: 99%

A BDNF-TrkB autocrine loop enhances senescent cell viability

Anerillas

Herman²,

Munk

et al. 2022

Preprint

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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 selectively capable of triggering apoptosis of senescent, but not proliferating, human fibroblasts. 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, including increased expression of BCL2L2 downstream of BDNF-TrkB, favoring senescent cell survival. Strikingly, 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.

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“…In this model, the elimination of SCs and decreased inflammation were shown by reduced amounts of SA-β-gal positive cells and mRNA levels of p16 INK4A , Bcl-2, IL-la, and IL-1β. It would be interesting if also chronic obstructive pulmonary disease (COPD), in which senescent cells are known to accumulate, were alleviated by senolytic treatment [ 83 ].…”

Section: Selected Examples Of Senopathies and Their Treatment With Se...mentioning

confidence: 99%

Senopathies—Diseases Associated with Cellular Senescence

2023

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Cellular senescence describes a stable cell cycle arrest state with a characteristic phenotype. Senescent cells accumulate in the human body during normal aging, limiting the lifespan and promoting aging-related, but also several non-related, pathologies. We propose to refer to all diseases whose pathogenesis or progression is associated with cellular senescence as “senopathies”. Targeting senescent cells with senolytics or senomorphics is likely to mitigate these pathologies. Examples of senopathies include cardiovascular, metabolic, musculoskeletal, liver, kidney, and lung diseases and neurodegeneration. For all these pathologies, animal studies provide clear mechanistic evidence for a connection between senescent cell accumulation and disease progression. The major persisting challenge in developing novel senotherapies is the heterogeneity of senescence phenotypes, causing a lack of universal biomarkers and difficulties in discriminating senescent from non-senescent cells.

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Breathe it in – Spotlight on senescence and regeneration in the lung

Cited by 7 publications

References 86 publications

A BDNF-TrkB autocrine loop enhances senescent cell viability

A BDNF-TrkB autocrine loop enhances senescent cell viability

A BDNF-TrkB autocrine loop enhances senescent cell viability

Senopathies—Diseases Associated with Cellular Senescence

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