Today, a pair of papers that are representative of present interest in the deeper mechanisms of cellular senescence. Senescent cells have of late become a major focus in the aging research community, now that scientists are largely convinced that (a) accumulation of these cells is a significant cause of aging, and (b) removing them can reverse aging and age-related disease to a large enough degree to justify significant investment in further development. Better late than never! The evidence has been compelling for decades, but only in 2011 was sufficient funding raised by a sufficiently well-regard research group to build an animal study of senescent cell clearance that the rest of the scientific community found compelling. This could all have happened ten or twenty years earlier, given different people in charge of budgets and strategies.
Still, here we are now. There is presently something of a gold rush underway in the research and development communities when it comes to the biochemistry of cellular senescence. Even setting aside more direct approaches such as suicide gene therapies or immunotherapies capable of targeting senescent cells for destruction, researchers have discovered at least four plausible mechanisms and associated drug candidates that can intervene in the peculiar biochemistry of these cells in order to nudge them into apoptosis and self-destruction. Companies have been founded to develop small molecule drugs based on a couple of these mechanisms, and hundreds of millions of dollars have been raised for clinical development. There is the sense that any similar new discovery will open the same sort of doors for its discoverers, and the expectation that many more useful mechanisms will be discovered.
Destruction of senescent cells is not the only goal in the research community. Other groups are more interested in preventing senescence from taking place, or in trying to modulate the harmful inflammatory signaling that allows a small number of senescent cells to cause widespread disruption of tissue function. I think that both of these are inferior approaches, because senescence is a mark of damage and why keep damaged cells around on the one hand, and on the other safely altering this poorly understood and diverse cell signaling is a vast, enormously complex project. Nonetheless, there will still be funding readily available for those groups that make discoveries in this field, at least until a few attempts at producing clinical therapies along these lines fail to do as well as the more direct approach of just destroying these unwanted cells. That is the way I expect matters to progress, in any case.
Senescent cells display the senescence-associated secretory phenotype (SASP) which plays important roles in cancer, aging, etc. Cell surface-bound IL-1α is a crucial SASP factor and acts as an upstream regulator to induce NF-κB activity and subsequent SASP genes transcription. IL-1α exports to cell surface via S100A13 protein-dependent non-classical secretory pathway. However, the status of this secretory pathway during cellular senescence and its role in cellular senescence remain unknown.
Here, we show that S100A13 is upregulated in various types of cellular senescence. S100A13 overexpression increases cell surface-associated IL-1α level, NF-κB activity, and subsequent multiple SASP genes induction, whereas S100A13 knockdown has an opposite role. We also exhibit that Cu2+ level is elevated during cellular senescence. Lowering Cu2+ level decreases cell surface-bound IL-1α level, NF-κB activity, and SASP production. Further, impairment of the non-classical secretory pathway of IL-1α delays cellular senescence.
d-amino acid oxidase (DAO) is a flavin adenine dinucleotide (FAD)-dependent oxidase metabolizing neutral and polar d-amino acids. Unlike l-amino acids, the amounts of d-amino acids in mammalian tissues are extremely low, and therefore, little has been investigated regarding the physiological role of DAO. We have recently identified DAO to be upregulated in cellular senescence, a permanent cell cycle arrest induced by various stresses, such as persistent DNA damage and oxidative stress. Because DAO produces reactive oxygen species (ROS) as byproducts of substrate oxidation and the accumulation of ROS mediates the senescence induction, we explored the relationship between DAO and senescence.
The accumulation of ROS is widely observed in senescence induced by various types of stress. ROS can hasten senescence through induction of oxidative DNA damage, and a recent study has shown that a positive feedback loop between ROS production and DNA damage response establishes senescence with the contribution of p21. Although ROS are reported to mediate p53-dependent cell cycle arrest, the mechanism by which p53 regulates ROS production in the process of senescence induction remains mostly unclear. We have recently identified DAO to be up-regulated specifically in senescent cells and shown the direct transcriptional regulation of DAO by p53.
In the present study, we evaluated the functional association of DAO with the senescence process. We revealed that DAO accelerates senescence via enzymatic generation of ROS and that d-arginine, a substrate for DAO, is abundantly present in cultured cancer cells. DAO is activated in response to DNA damage presumably due to an increase in availability of its coenzyme, FAD.