Groups such as the University of Tokyo, Kyushu University, Niigata University, Keio University, and National Center for Longevity Medical Research have found that inhibitors targeting glutamine metabolism remove aging cells and improve aging, senile diseases, and lifestyle diseases. Clarified to do.
Previous studies have shown that genetic engineering removal of senescent cells showing irreversible arrest of proliferation that accumulates in the body with aging extends healthy life expectancy and improves the pathophysiology of age-related diseases. I know it will be.However, recently, it has become clear that senescent cells have diversity, and a method for removing a wide range of senescent cells has not been developed.
As a result of constructing a new pure culture method for senescent cells and searching for genes essential for survival using purified senescent cells, this group succeeded in identifying GLS1 which is a glutamine-metabolizing enzyme.Analysis of GLS1 expression in senescent cells revealed that the expression level of GLS1 also increased with age in human skin.
Furthermore, in aged cells, the lysosomal membrane is damaged, and when the intracellular pH decreases due to this, the amount of GLS1 is increased to produce ammonia, which regulates the homeostasis of the intracellular pH and maintains survival. On the contrary, it was also found that inhibition of GLS1 significantly lowers the intracellular pH and induces cell death.In fact, when a GLS1 inhibitor was administered to aged mice, senescent cells died in various tissues and organs, and the aging phenomenon was significantly improved.In addition, administration of a GLS1 inhibitor to age-related disease model mice alleviated the symptoms of obese diabetes, arteriosclerosis, and non-alcoholic fatty liver.
From this result, it was clarified that the enhancement of glutamine metabolism due to the damage of the lysosomal membrane of senescent cells leads to the sensitivity to GLS1 inhibition, and the GLS1 inhibitor targeting this is effective for the removal of senescent cells.Using this research as a foothold, it is expected to lead to the development of innovative anti-aging therapies and preventive / therapeutic agents for senile diseases and lifestyle-related diseases.
Paper information:[Science] Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders
