Targeting Apoptotic Signaling versus Targeting Mitochondrial Abnormalities to Destroy Senescent Cells
This review paper contrasts two classes of approach to senolytic therapies that selectively target senescent cells for destruction. Inducing apoptosis in senescent cells by disrupting the balance between pro-apoptotic and anti-apoptotic signaling should be familiar to this audience, as it is the basis of some of the first senolytic drugs discovered, such as navitoclax. The other approach is more novel and less well explored, being the targeting of abnormalities in mitochondrial function that are peculiar to senescent cells. In order to be selective, any senolytic approach must exploit some difference between senescent cells and normal cells. It is interesting to see the list of those exploitable differences grow as researchers put more effort into mapping the biochemistry of cellular senescence.
Senescent cells with replicative arrest can be generated during genotoxic, oxidative, and oncogenic stress. Long-term retention of senescent cells in the body, which is attributed to highly expressed BCL-family proteins, chronically damages tissues mainly through a senescence-associated secretory phenotype (SASP). It has been documented that accumulation of senescent cells contributes to chronic diseases and aging-related diseases.
Despite the fact that no unique marker is available to identify senescent cells, increased p16INK4a expression has long been used as an in vitro and in vivo marker of senescent cells. We reviewed five existing p16INK4a reporter mouse models to detect, isolate, and deplete senescent cells. Senescent cells express high levels of anti-apoptotic and pro-apoptotic genes compared to normal cells. Thus, disrupting the balance between anti-apoptotic and pro-apoptotic gene expression, such as ABT-263 and ABT-737, can activate the apoptotic signaling pathway and remove senescent cells.
Mitochondrial abnormalities in senescent cells were also discussed, for example mitochondrial DNA mutation accumulation, dysfunctional mitophagy, and mitochondrial unfolded protein response (mtUPR). The mitochondrial-targeted tamoxifen, MitoTam, can efficiently remove senescent cells due to its inhibition of respiratory complex I and low expression of adenine nucleotide translocase-2 (ANT2) in senescent cells. Therefore, senescent cells can be removed by various strategies, which delays chronic and aging-related diseases and enhances lifespan and healthy conditions in the body.