Senescent cells accumulate in organs as they age, trigger severe intolerance, and cause a number of age-related diseases such as cancer. The cells rise through a process called “cell senescence,” a permanent cell cycle arrest as a result of multiple stresses.
A collaborative research group led by Professor Makoto Nakanishi of the Institute of Medical Science, University of Tokyo (IMSUT), and co-researchers has identified an inhibitor of the metabolic enzyme glutamate GLS1so that its administration inhibits selectively in vivo senescent cells.
They confirmed that the GLS1 inhibitor eliminated senescent cells from various organs and tissues in aged mice, reducing age-related stress dysfunction and symptoms of obesity, arteriosclerosis, and NASH. The results of this research were published in “Science“on January 15, 2021.
Previous studies have shown that genetic engineering removing senescent cells from aged mice delays the onset of geriatric diseases such as arteriosclerosis and kidney damage and extends healthy life expectancy. However, these studies have not led to the identification of useful drug candidates.
Our findings can contribute to the development of new anti-aging therapies that remove senescent cells by targeting the metabolic properties of those cells. “
Makoto Nakanishi, Professor, Institute of Medical Science, University of Tokyo (IMSUT)
Lysosomal membranes hold the key to senescent cell removal
The research team has developed a new method for making purified senescent cells to find genes that are essential for senescent cell survival. This new method activates the p53 gene in the G2 phase, which can effectively stimulate cell senescence.
They used purified senescent cells to find genes necessary for senescent cell survival, then identified GLS1, which is involved in glutamine metabolism, as a potential candidate gene.
When they studied the effect of GLS1 inhibitor on senescent cell mortality, senescent cells were more sensitive to GLS1 inhibition due to damage to the lysosomal membrane and reduced intracellular pH. When administering GLS1 inhibitors to aged mice, senescent cells in several tissues and organs were removed, and the aging feature was significantly improved.
Organelles are called lysosomes to play an essential role in the regulation of intracellular pH. The team analyzed the dynamics of lysosomes and found the crucial fact that damage to the lysosomal organs in senescent cells reduces intracellular pH.
Expectations for innovative anti-aging therapies and treatments for geriatric diseases
The results of this study show more interesting results. As age progresses, motor activity declines due to muscle loss, and metabolic disorders due to adipose tissue atrophy occur.
However, when the research team implanted GLS1 inhibitors into mice suffering from age-related disorders, the progression of these age-related symptoms was reversed. In addition, GLS1 inhibitors were able to relieve the symptoms of obesity, arteriosclerosis, and NASH.
According to the team, GLS1 inhibitors are currently in clinical trials as effective cancer treatments. “We hope to develop innovative anti-aging treatments and therapies for geriatric diseases that remove senescent cells by treatment with GLS1 inhibitors,” Dr. Nakanishi said.
Source:
Institute of Medical Science, University of Tokyo
Magazine Reference:
Johmura, Y., et al. (2021) Senolysis with glutaminolysis inhibition reduces a number of age-related disorders. Science. doi.org/10.1126/science.abb5916.