Inhibition of GLS1 Selectively Destroys Senescent Cells
Senescent cells accumulate with age, and this accumulation is an important cause of age-related dysfunction and disease. Clearing senescent cells from old animals produces rejuvenation, and human trials of first generation senolytic drugs capable of selectively destroying senescent cells are underway for a number of age-related conditions. Meanwhile, an ever increasing number of research groups are delving deeper into the biochemistry of cellular senescence, in search of novel differences between senescent and non-senescent cells that can be exploited in order to selectively destroy senescent cells in new and hopefully better ways. New approaches continue to be uncovered, as illustrated by the research materials noted here.
Senescent cells accumulate in organs during aging, promote tissue dysfunction, and cause numerous aging-related diseases like cancer. The cells arise through a process called "cellular senescence," a permanent cell cycle arrest resulting from multiple stresses. Researchers have identified an inhibitor of the glutamate metabolic enzyme GLS1 so that its administration selectively eliminates senescent cells in vivo. They confirmed that the GLS1 inhibitor eliminated senescent cells from various organs and tissues in aged mice, ameliorating age-associated tissue dysfunction and the symptoms of obese diabetes, arteriosclerosis, and NASH.
The research team has developed a new method for producing purified senescent cells to search for genes essential for senescent cells' survival. This new method activates the p53 gene in the G2 phase, which can efficiently induce cellular senescence. They used purified senescent cells to search for genes essential for senescent cells' survival, then identified GLS1, which is involved in glutamine metabolism, as a potential candidate gene.
When they examined the effect of GLS1 inhibition on the mortality of senescent cells, senescent cells were more sensitive to GLS1 inhibition due to damage to the lysosomal membrane and decreased intracellular pH. The organelles called lysosomes play an essential role in the regulation of intracellular pH. The team analyzed the dynamics of lysosomes and found the vital fact that damage to the lysosomal membranes in senescent cells lowers intracellular pH. When they administered GLS1 inhibitors to aged mice, senescent cells in various tissues and organs were removed, and the aging phenomenon was significantly improved.
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