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Review
. 2017 Jul:21:21-28.
doi: 10.1016/j.ebiom.2017.04.013. Epub 2017 Apr 12.

Cellular Senescence: A Translational Perspective

James L Kirkland  1 , Tamara Tchkonia  2
Affiliations
Review

Cellular Senescence: A Translational Perspective

James L Kirkland et al. EBioMedicine. 2017 Jul.

Abstract

Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). Senescent cells accumulate in various tissues with aging and at sites of pathogenesis in many chronic diseases and conditions. The SASP can contribute to senescence-related inflammation, metabolic dysregulation, stem cell dysfunction, aging phenotypes, chronic diseases, geriatric syndromes, and loss of resilience. Delaying senescent cell accumulation or reducing senescent cell burden is associated with delay, prevention, or alleviation of multiple senescence-associated conditions. We used a hypothesis-driven approach to discover pro-survival Senescent Cell Anti-apoptotic Pathways (SCAPs) and, based on these SCAPs, the first senolytic agents, drugs that cause senescent cells to become susceptible to their own pro-apoptotic microenvironment. Several senolytic agents, which appear to alleviate multiple senescence-related phenotypes in pre-clinical models, are beginning the process of being translated into clinical interventions that could be transformative.

Keywords: A1155463; A1331852; Dasatinib; Fisetin; Navitoclax; Quercetin; SASP inhibitors; Senescent Cell Anti-apoptotic Pathways (SCAPs); Senolytics.

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Figures

Fig. 1
Fig. 1
Inducers, mediators, SCAPs, the SASP, and effects of senescent cells. Cellular senescence is a cell fate that, like replication, differentiation, or apoptosis, is 1) induced by a range of intra- or extracellular stimuli or combinations of them, 2) mediated by a cascade of transcriptional regulators that affect expression of multiple downstream target genes, and 3) associated with widespread changes in chromatin structure. Senescence takes days to weeks to become fully established and changes in quality over time. Senescent Cell Anti-apoptotic Pathways (SCAPs) shield senescent cells from their own pro-apoptotic SASP. These SCAPs constitute the Achilles' heel of senescent cells (Zhu et al., 2015b) that have turned out to be the critical key for developing the senolytic drugs and peptides discovered so far.
See this image and copyright information in PMC

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