The aging process is known to be caused mainly by 9 factors (cited from López-Otín et. al. 2013). These factors do not affect aging independently but influence each other complicatedly. For example, genomic instability, Epigenetic alterations, and telomere attrition are known to cause cellular senescence. The cell that has undergone cellular senescence becomes a senescent cell.

Cells are exposed to various genomic stresses, both internal and external. Even under stress, cells have self-repair mechanisms and repair the damage quickly. However, when the stress is too severe to repair, it is known to induce apoptosis or cellular senescence. It is known that senescent cells are characterized as permanently arresting cell proliferation by expressing the cell cycle arrest factor p16 and secreting inflammatory substances.

Recently, a mouse model has been established in which cells expressing p16, a marker gene for senescent cells, can be eliminated using genetic engineering. Analysis of these mice showed that the removal of senescent cells improves various age-related diseases and extends a healthy life span, indicating that cellular senescence plays an important role in age-related alterations (Baker et.al. 2011 & 2016). Therefore, senolysis has the potential to completely cure various age-related diseases that have been previously untreatable, and is currently attracting a great deal of attention.

Most of the research on senescent cells was performed in vitro because there were no tools available to identify and isolate senescent cells in vivo. There was a lack of knowledge about senescent cells in vivo. Therefore, we established a new mouse model in which senescent cells (p16-positive cells) can be visualized at the single-cell level in a time-specific manner. We found that senescent cells in vivo have the same characteristics as senescent cells in vitro and various types of cells can become senescent cells. In addition, the elimination of senescent cells was shown to inhibit the progression of nonalcoholic steatohepatitis (NASH).

One of the ways to achieve the elimination of senescent cells is to identify the survival maintenance mechanism working only in senescent cells and to stop this mechanism. Therefore, we established an shRNA library screening system in senescent cells to identify genes that are necessary for the survival of senescent cells. As a result, we found that the glutamine-metabolizing enzyme GLS1 is specifically essential for the survival of senescent cells. Furthermore, we showed that the administration of a GLS1 inhibitor can eliminate senescent cells in vivo and ameliorate various age-related alterations.

Another way to find senolytic drugs is through compound screening. However, the number of compounds that can theoretically be synthesized is said to be 10 to the 60th power, which means that it is impossible to screen all compounds. Therefore, we focused on a machine learning method called Chemprop. In 2020, Collins Lab successfully used Chemprop to search for new antibiotics, and this method may be used to find new senolytic drugs. Indeed, we have successfully obtained several senolytic drugs. This research is currently ongoing.