Thread by @MartinBJensen

Time to catch up on some #Senescence papers, starting with beautiful work by @corina_amor_MD, Judith Freucht & @JosefLeibold. They used #CART #CellTherapy to clear #Senescent cells, and you'll never guess what happened next! nature.com/articles/s4158…

Just kidding, you guessed it: disease model mice got better. Props to the authors for A) inducing #Senescence in 3 different ways, B) using 2 models of #NASH/liver #Fibrosis, and C) validating their senescence observations in human samples of #Cancer and #Atherosclerosis.

The linchpin of the paper was identifying a specific membrane marker on #Senescent cells, uPAR. They used bulk #Transcriptomics to identify candidates, then narrowed down with #Proteomic data. Go #Omics!
They didn't explore whether uPAR is causative for the #Senescent phenotype.

What's the context for this #CellTherapy?
As a core #AgingPathway, #Senescence is implicated in >1 #DiseasesOfAging, most of them untreatable. #Senolytics have 3 options: 1st drug for a big unmet need / a drug that could treat multiple diseases / treat #Aging to PREVENT disease.

Companies like @UnityBiotech are racing #SmallMolecule #Senolytics to market, aiming at goal 1 and maybe 2. But early compounds could have side effects precluding systemic treatment.
#CellTherapy has cost/scaling concerns, but could feasibly be imagined to achieve goals 2 and 3.

Either way, you would want a #Senolytic with a short-ish half-time, and redose. #Senescent cells are already known to function in regeneration, and other functions may still be discovered. And this applies equally for specific targets like uPAR, which may not be fully specific.

Main caveat for the paper is that it's all done in young animals. This is a POC paper and I don't fault the authors, but everything will be harder in realistic, aged models (let alone humans). And that's where you most need the therapy to work.

E.g. one experiment needed immunodeficient mice bc "normal mice cleared all #Senescent cells naturally". So will the #CellTherapy still work with an #Aged, dysfunctional immune system? For #DiseasesOfAging, it's both difficult and critical to make drugs work in that environment.