At this moment in history, the study of the biology of aging frequently brings us new discoveries, and today is no exception. Researchers have discovered a new drug that appears to destroy lingering senescent cells, and it achieves this without using any of the previously known mechanisms or pathways normally associated with inducing cell destruction.
What are senescent cells?
As you age, increasing numbers of your cells enter into a state known as senescence. Senescent cells do not divide or support the tissues of which they are part; instead, they emit a range of potentially harmful chemical signals that encourage nearby healthy cells to enter the same senescent state. Their presence causes many problems: they reduce tissue repair, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related diseases.
Senescent cells normally destroy themselves through a self-destruct process called apoptosis, and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of senescent cells escape this process and begin to accumulate in all the tissues of the body.
By the time people reach old age, significant numbers of these senescent cells have accumulated in our tissues and organs, causing chronic inflammation and damage to surrounding cells and tissue. The accumulation of senescent cells is thought to be one of the reasons we age.
The proposed solution to the problem of senescent cell accumulation is to cause them to stop resisting and initiate apoptosis; drugs that can tip senescent cells over the edge and destroy themselves are known as senolytics.
SYK inhibitors appear to destroy senescent cells, but we don’t know how
In the journal Aging, the researchers of a new study have published their discovery of a new senolytic compound, which, intriguingly, does not use any of the currently known mechanisms or pathways to induce apoptosis [1].
The current generation of senolytic compounds focus on known pathways such as p53 and the BCL-2 family in order to cause death-resistant senescent cells to self-destruct. While these researchers do not fully understand the mechanism, they show that R406, an SYK inhibitor, does appear to induce apoptosis.
Spleen tyrosine kinase (SYK) is mainly expressed by hematopoietic cells, a population of bone marrow stem cells that give rise to other blood cells during a process called haematopoiesis. SYK plays a key role in the B-cell receptor signaling pathway and is also an important component in signal transduction from other immune receptors, such as Fc and adhesion receptors.
There are currently a number of SYK inhibitors, including the thrombocytopenia drug fostamatinib, the cancer drug entospletinib, and the cancer drug cerdulatinib. R406 is an orally bioavailable SYK inhibitor and has been shown in early mouse studies and human studies to reduce Immune system-mediated inflammation; in human trials, it was shown to inhibit activation of basophils and thus reduce inflammation [2]. The data also suggest that it can also influence other types of immune cells, such as macrophages and B-cells.
The selective removal of senescent cells by senolytics is suggested as a potential approach to reverse aging and extend lifespan. Using high-throughput screening with replicative senescence of human diploid fibroblasts (HDFs), we identified a novel senolytic drug R406 that showed selective toxicity in senescent cells. Using flow cytometry and caspase expression analysis, we confirmed that R406 caused apoptotic cell death along with morphological changes in senescent cells. Interestingly, R406 altered the cell survival-related molecular processes including the inhibition of phosphorylation of the focal adhesion kinase (FAK) and p38 mitogen-activated protein kinase (MAPK) in senescent cells. This pattern was not observed in other known senolytic agent ABT263. Correspondingly, apoptotic cell death in senescent cells was induced by simultaneously blocking the FAK and p38 pathways. Taken together, we suggest that R406 acts as a senolytic drug by inducing apoptosis and reducing cell attachment capacity.
Conclusion
The exact method by which R406 appears to have a senolytic effect is currently unknown; however, its ability to reduce immune system-mediated inflammation may be improving the function of the immune system, thus preventing the excessive and detrimental activation of immune cells.
The immune system is known to become dysfunctional during aging at least in part due to excessive exposure to the chronic, systemic inflammation known as inflammaging, so it could be reducing senescent cell burden by making the immune system better at locating and destroying senescent cells more efficiently.
Like all things in biology, it is just a matter of time before the exact pathways and mechanism are discerned, but the discovery of a potential new group of senolytic drugs is great news.
Literature
[1] Cho, H. J., Yang, E. J., Park, J. T., Kim, J. R., Kim, E. C., Jung, K. J., … & Lee, Y. S. (2020). Identification of SYK inhibitor, R406 as a novel senolytic agent. Aging, 12.
[2] Braselmann, S., Taylor, V., Zhao, H., Wang, S., Sylvain, C., Baluom, M., … & Wong, B. R. (2006). R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. Journal of Pharmacology and Experimental Therapeutics, 319(3), 998-1008.
