APLS1 Inhibitors Eliminate Senescent Cells to Ameliorate Ageing
A new technique has been developed to eliminate senescent cells that are involved in many age-related diseases, according to a study by researchers at the University of Tokyo.
As ageing progresses, cancers emerge, motor function declines through muscle loss, and metabolic disorders occur due to adipose tissue atrophy. Senescent cells accumulating in organs are behind many of these problems; their telomeres having shortened through divisions as a result of multiple stresses and now at their replication limit, they now no longer function effectively. Previous research using genetic engineering to knock out senescent cells in mice was able to put the onset of age-related diseases such as arteriosclerosis and renal damage, and extended life expectancy. However, the research did not yield a drug which could be given as a treatment.
To tackle this problem, the researchers created a way to produce large numbers of purified senescent. cells to search for genetic targets for drugs. One of the ways they found involved GLS1, a gene involved in glutamine. On testing with GLS1 inhibitors, senescent cells were vulnerable due to damage to the lysosomal membrane and lower intracellular pH. Lysosomes are organelles which produce enzymes to destroy defunct cell parts, bacteria and viruses if needed, and the cell itself if apoptosis is triggered. They also have an essential role in the regulation of intracellular pH, and are very acidic, having to be protected from the rest of the cell by a membrane. Analysing the dynamics of lysosomes, the team found that damage to the lysosomal membranes in senescent cells decreases intracellular pH.
When they administered GLS1 inhibitors to old mice, knocking out senescent cells, their ageing was significantly improved. The symptoms of obese diabetes, arteriosclerosis, and fatty liver disease were ameliorated. GLS1 inhibitors are already being used in trials as cancer treatments.
“We hope that innovative anti-aging therapies and treatments for geriatric diseases will be developed that can remove senescent cells by treatment with GLS1 inhibitors,” said Professor Nakanishi.
Source: News-Medical.Net
Journal information: Johmura, Y., et al. (2021) Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science. doi.org/10.1126/science.abb5916.
