Fight Aging!

Cellular senescence is an evolutionary adaptation of a mechanism of embryonic development that serves to to suppress cancer incidence. Cells that become senescent in response to damage or a toxic environment cease to divide, and usually go on to self-destruct or be destroyed by the immune system, which serves to remove from the picture those cells most at risk of becoming cancerous. Unfortunately, that isn't all they do, and not all are destroyed. Some fraction of senescent cells linger and accumulate to cause widespread harm in the body, despite their small numbers, through the secretion of various signal molecules. These signals produce chronic inflammation, damage the fine structure of tissue by remodeling the extracellular matrix, and alter the behavior of surrounding cells for the worse. They are one of the root causes of aging and age-related disease. While the primary, and I think most effective, approach to dealing with senescent cells as a cause of aging is to destroy them, a sizable contingent of researchers are more interested in finding ways to alter the behavior of these cells. This includes cancer researchers who would like to see more cellular senescence rather than less as a way to combat cancers. These researchers believe that by modulating senescent signaling, senescent cells can in principle be rendered largely harmless. This, however, is a long road in comparison to simply destroying the unwanted cells. Senescent cell signaling is by no means fully mapped or understood, and considerable effort to damp one type of signal would still leave all of the rest. Meanwhile, senescent cell destruction is forging ahead to towards clinical translation quite rapidly.

Cellular senescence is a state in which normal healthy cells do not have the ability to divide. Senescence can occur when cancer-causing genes are activated in normal cells or when chemotherapy is used on cancer cells. Thus, senescence induces a mechanism that halts the growth of rapidly dividing cells. Once thought to only be beneficial to halt cancer progression, work has shown that during senescence there is an increase in secreted factors called cytokines and chemokines (small proteins important in immune responses) that may have detrimental, pro-tumorigenic side effects. Researchers have identified a protein that plays a critical role in the expression of cytokines and chemokines, and that decreasing this protein suppresses the expression of these secreted factors. This suggests that there may be ways of promoting the positive effects of senescence while suppressing its negative effects.

The researchers focused on chromatin, a cellular structure responsible for holding the DNA in our cells together. During senescence, some of the chromatin is reorganized into senescence-associated heterochromatin foci (SAHF). When this happens, genes that are responsible for promoting proliferation are silenced. However, the expression of cytokine and chemokine genes - known collectively as the senescence-associated secretory phenotype (SASP) - is increased. "When senescence happens, you have two closely linked phenomena occurring, yet one of these helps to halt tumor progression while the other causes an increase in potentially harmful inflammatory cytokines and chemokines. We pinpointed the architecture of chromatin and the proteins that influence chromatin organization as the proper place to start to try and solve this paradox."

The scientists looked at a set of proteins known as high mobility group proteins, which are responsible for altering chromatin architecture in order to regulate gene transcription. One such protein called high mobility group box 2 (HMGB2) binds to DNA to increase chromatin's accessibility to transcription factors. They showed that HMGB2 promotes SASP gene expression by preventing the spreading of heterochromatin and therefore preventing SAHF from silencing SASP genes. When the researchers silenced HMGB2, SASP genes were successfully silenced by SAHF, suggesting that the detrimental effects of senescence might be negated by inhibiting HMGB2. "Understanding senescence is critical for understanding how tumor growth can be successfully suppressed. With the information from this study, we may be able to increase the effectiveness of chemotherapeutic agents that are able to induce senescence by silencing HMGB2 and decreasing the expression of unwanted secreted factors."

Link: https://www.wistar.org/news-and-media/press-releases/key-protein-implicated-negative-side-effects-senescence