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.



It would be nice if a humble small molecule inhibitor could wipe out senescent cells. Small molecules have some advantages, they have a great tissue distribution and the immune system doesn't react to them as easy.

Posted by: Tom at February 12th, 2021 9:26 AM

Interesting. Do we have an estiamte what percentage of ScC were removed and how much improvement was witnessed compared to other protocols and CR?

Posted by: Cuberat at February 12th, 2021 12:41 PM

small molecule drugs have the benefit that they do fit nicely in our big Pharma paradigm and can get financing and be steamrolled into production albeit with the applicable level I-III delays and costs...

Posted by: Cuberat at February 12th, 2021 12:43 PM

Hi everyone. Does anybody know whether there are techniques available nowadays to measure level/ quantity of senescent cells in a tissue before and after a treatment?

Posted by: Alek Ales at February 12th, 2021 2:46 PM

@Cuberat: If you take their report at face value, they eliminated essentially *all* of the senescent cells in kidney, lung, liver, and intra-abdominal adipose. They did test multiple senescence and SASP measures in parallel (e.g. p16 mRNA, lamin B1, SA-b-gal, IL-6), and showed consistent results.

@Alek Ales: Typically senescent cell quantities are determined via combinations of measurements (e.g. increased SA-b-galactosidase, upregulation of CDK-inhibitor proteins like p16 and p21, decreased proliferation markers like Ki-67, increased markers of SASP like IL-6, loss of nuclear lamin B1 and nuclear HMGB1). The ICSA consensus statement is worth looking at:

Posted by: Edward Greenberg at February 12th, 2021 6:14 PM

When can bio-hackers get some?

Posted by: Tiny Mouse at February 12th, 2021 10:46 PM

Hmm. I read somewhere that mice don't get arteriosclerosis?

Posted by: Matt at February 13th, 2021 6:59 AM

Would a person actually want to block glutaminase? You'd be seriously impeding ATP production.

Posted by: Mark at February 15th, 2021 4:30 AM

It's seems that discovery of a new mechanism of telomere lengthening in T cells (lymphocytes B giving snippets of telomere up to 3000 pair length to lymphocytes T) puts all the previous studies on blood telomere lenght and (lack of) correlation with age into dustbin.

It's seems that the shortest telomeres putting cells into senescence as early as late 30-ties/early 40-ties and lingering senescent cells multiplying in number about that age and producing TGF-beta which blocks telomerase it's painfully and forefront life length limiting factor. Let's fight senescent cells!

Posted by: SilverSeeker at February 17th, 2021 7:50 AM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.