Systematic Screening of Cell Death Pathways in Search of New Senolytics

Senolytic drugs capable of clearing senescent cells from the bodies of older people will be a very important part of the medicine of tomorrow. A burden of senescent cells contributes significantly to aging, and removing them produces quite rapid and profound rejuvenation in animal models. If taking the small molecule drug approach, a diversity of senolytics will likely be needed in order to clear most senescent cells from most tissues, due to differences in drug biodistribution and biochemistry of senescence between tissue types. The search for new senolytic drug targets and drug compounds has been underway in earnest for a few years, and researchers are starting to become more rigorous and systematic, as demonstrated here.

Selectively ablating senescent cells ("senolysis") is an evolving therapeutic approach for age-related diseases. Current senolytics are limited to local administration by potency and side effects. While genetic screens could identify senolytics, current screens are underpowered for identifying genes that regulate cell death due to limitations in screen methodology.

Here, we establish Death-seq, a positive selection CRISPR screen optimized to identify enhancers and mechanisms of cell death. Our screens identified synergistic enhancers of cell death induced by the known senolytic ABT-263, a BH3 mimetic. SMAC mimetics, enhancers of cell death in our screens, synergize with ABT-199, another BH3 mimetic that is not senolytic alone, clearing senescent cells in models of age-related disease while sparing human platelets, avoiding the thrombocytopenia associated with ABT-263.

In summary, Death-seq enables the systematic screening of cell death pathways to uncover molecular mechanisms of regulated cell death subroutines and identify drug targets for diverse pathological states such as senescence, cancer, and neurodegeneration.



You had me at "systematic screening..."

We need a lot more automatic exploration of the cell.

Posted by: Matt at April 11th, 2022 10:28 AM

What amazes me that despite the early success in identifying potent senolytics a few years ago , we still don't have anything better than fisetin and dasatinib+quercetin.

I understand that the short-hanging fruits were picked quickly. But after several years and many (probably) hundreds of researchers digging in that directions I would expect to have a new senolytic at least every year.

Posted by: Cuberat at April 11th, 2022 10:38 AM

@Cuberat: Multiple new senolytics have been found every year for the past few years. That is happening. Dasatinib and quercetin is a high bar to beat, however. I'm sure many of the senolytics companies can do better with their more engineered technologies, but those will be very hard to access for the foreseeable future.

Posted by: Reason at April 11th, 2022 1:28 PM

That's my point exactly. How come D+Q , which was meant to be a proof of concept is such an insurmountable competitor to pass. After all, thus combo is neither that good not selective. The only big development, except OISIN, was the introduction of pro-drugs. And there I fail to find a study trying prodrug conjugated dasatinib with quercetin.

Of course, penicillin is still one of the strongest antibiotics available, barring resistance. The first discovery happens to be arguably the best.
So it might turn out that d+q is close to the optimum for a diverse set of senescent cells. This would be highly surprising, however.

Posted by: Cuberat at April 11th, 2022 8:24 PM - looking at this list there are more than one discovered yearly. Looking at this site only... recently there were a few a year reported here. Many of them are better and safer than Q+D (at least in tube... that's it). The problem is with translating from the test tube into in vivo on human. It takes many years, and the cost and effort of coming from tube through all safety research into human trial. The ones with very long safety history of usage (of senolytic dose before) have a many years head start (like Q+D), with a very brief safety tests or no at all needed.

Posted by: SilverSeeker at April 13th, 2022 8:52 AM
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