Senescence and apoptosis: dueling or complementary cell fates?

Abstract

In response to a variety of stresses, mammalian cells undergo a persistent proliferative arrest known as cellular senescence. Many senescence-inducing stressors are potentially oncogenic, strengthening the notion that senescence evolved alongside apoptosis to suppress tumorigenesis. In contrast to apoptosis, senescent cells are stably viable and have the potential to influence neighboring cells through secreted soluble factors, which are collectively known as the senescence-associated secretory phenotype (SASP). However, the SASP has been associated with structural and functional tissue and organ deterioration and may even have tumor-promoting effects, raising the interesting evolutionary question of why apoptosis failed to outcompete senescence as a superior cell fate option. Here, we discuss the advantages that the senescence program may have over apoptosis as a tumor protective mechanism, as well as non-neoplastic functions that may have contributed to its evolution. We also review emerging evidence for the idea that senescent cells are present transiently early in life and are largely beneficial for development, regeneration and homeostasis, and only in advanced age do senescent cells accumulate to an organism's detriment.

Keywords: aging; apoptosis; cancer; embryogenesis; senescence.

Figure 1. Senescence in development and in the adult

During development and in the healthy adult, cells can undergo acute senescence, a permanent cell cycle arrest that is physiologically normal. In the embryo and placenta, these cells secrete signaling molecules as part of their SASP to promote morphogenesis. Cell death through immune clearance also complements cell death through apoptosis to change cellularity in developing tissues. In the adult, acute senescent cells function to suppress tumorigenesis and promote wound repair, using different molecular mechanisms than in the embryo. Upon immune dysfunction, acute senescent cells that would normally be cleared by immune surveillance may be chronically present. As they also have a decreased ability to stabilize p53 to the levels required for apoptosis, senescent cells not killed by the immune system may contribute to tumorigenesis and tissue dysfunction. See Glossary for definitions and the text for details.

Figure 2. Signaling pathways that enforce the choice between cell cycle arrest, senescence, and apoptosis

Pathways are colored as follows: leading to arrest in gray, leading to senescence in orange, and leading to apoptosis in red. The weight of the arrow reflects the level of stress. The p16-RB and p53-p21 pathways are known to be important for cellular response to stress. The decision to activate p16, p53, or both is determined by the stress level and cell type. Low levels of p16 promote a transient arrest, whereas high levels lead to senescence. Low levels of p53, with transient kinetics and K161/K162 acetylation, promote cell cycle arrest and senescence. High levels of p53, K117 acetylation, and cooperativity of DNA binding domains within the p53 tetramer lead to the transcription of apoptotic genes and ensuing apoptosis, both directly and by blocking pro-senescence signals. See Glossary for definitions and the text for details.

Figure 3. The interplay between senescence and apoptosis is cell type specific

The pathways leading to apoptosis are depicted in red, those leading to apoptosis resistance in orange, and those that sensitize endothelial cells to apoptosis in blue. (A) Senescent fibroblasts are resistant to p53-mediated apoptotic stimuli, such as actinomycin D and low-dose cisplatin, as well as to stimuli—such as staurosporine—that rely on p53 target genes. This resistance can be explained by low p53 levels due to decreased stabilization in senescent cells, as well as the existence of senescence-specific p53 post-translational modifications. Senescent and non-senescent cells have a similar sensitivity to p53-independent apoptotic stimuli. (B) Senescent endothelial cells have increased sensitivity to apoptosis. Senescent endothelial cells lose eNOS expression and express reduced levels of pro-survival NO. This eNOS loss may be due to the loss of the positive regulator AKT, or to the upregulation of negative regulators, such as caveolin-1. However, AKT levels increase during replicative senescence, so the issue of PTEN/PI3K/AKT signaling in the senescent endothelium is unresolved. See Glossary for definitions and the text for details.

Figure 4. Consequences of senescence and apoptosis in stressed tissues

Normal cells are subject to a variety of stressful stimuli, including oncogenic insults (top) and tissue damage (bottom). Cells that have acquired a pre-neoplastic lesion may undergo senescence or apoptosis. The outcome of this decision is largely the same if the senescence surveillance machinery—which ensures that the lesion is efficiently removed—is intact. If pre-neoplastic lesions do not induce senescence or apoptosis, they continue to grow and progress (middle). In this scenario, if senescence is engaged in a fraction of the now established tumor, the SASP and recruitment of the surveillance machinery may be much more effective at removing tumor cells than a single cell that undergoes apoptosis and does not initiate an immune response. Although not illustrated, if a large percentage of tumor cells are coerced into apoptosis, this would also lead to reduction in tumor volume. In response to tissue damage (bottom), senescence would also theoretically be advantageous compared to apoptosis, as the production of the SASP would limit tissue fibrosis and promote tissue remodeling, as long as the SASP-producing cell is ultimately removed by the immune system.