The Possibility of Senolytic Vaccinations to Control the Burden of Senescent Cells

Arguably the primary reason why the number of senescent cells increases with age throughout the body is the growing failure of the immune system to clear these errant cells. The reasons for that failure are not well understood in detail, though some inroads have been made into that area of research. Both the innate and adaptive immune system are involved in clearance of senescent cells, so in principle there should be a plethora of mechanisms that could be targeted in order to create immunotherapies that increase the pace at which the immune system clears senescent cells. Both SIWA Therapeutics and Deciduous Therapeutics are working on approaches to this goal.

Today's research materials discuss a different way forward. If senescent cells have surface features that are distinctive enough, not shared to a large degree with other cells, then it should be possible to immunize against one of those features, and have the adaptive immune system vigorously attack senescent cells for an extended period of time, perhaps years or more. Such surface features should exist, because the immune system does in fact recognize and clear senescent cells. The work of SIWA Therapeutics is based on use of a specific set of surface features, but it seems likely that there will be variance in such features from tissue to tissue. The paper I point out today focuses on one tissue only, the vascular endothelium, as the researchers involved are interested in the role of cellular senescence in the progression of atherosclerosis. Their findings may or may not generalize to any other tissues.

Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice

Elimination of senescent cells (senolysis) was recently reported to improve normal and pathological changes associated with aging in mice. However, most senolytic agents inhibit antiapoptotic pathways, raising the possibility of off-target effects in normal tissues. Identification of alternative senolytic approaches is therefore warranted. Here we identify glycoprotein nonmetastatic melanoma protein B (GPNMB) as a molecular target for senolytic therapy. Analysis of transcriptome data from senescent vascular endothelial cells revealed that GPNMB was a molecule with a transmembrane domain that was enriched in senescent cells (seno-antigen). GPNMB expression was upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis.

Genetic ablation of Gpnmb-positive cells attenuated senescence in adipose tissue and improved systemic metabolic abnormalities in mice fed a high-fat diet, and reduced atherosclerotic burden in apolipoprotein E knockout mice on a high-fat diet. We then immunized mice against Gpnmb and found a reduction in Gpnmb-positive cells. Senolytic vaccination also improved normal and pathological phenotypes associated with aging, and extended the male lifespan of progeroid mice. Our results suggest that vaccination targeting seno-antigens could be a potential strategy for new senolytic therapies.


Mmm the problem of this approach is that it will prevent the useful functions of senescent cells, like in wound healing.

Posted by: Antonio at December 18th, 2021 2:50 AM

It remains to be seen what will be the trade-off. Periodic cleanup sounds safer but there might be some tissues where a constant immune abrasion might be desirable.

What is also interesting that the vaccine at the end child be relatively cheap on the other of phiser and moderna COVID.
So if it is quite targeted minty be worth it

Posted by: Cuberat at December 18th, 2021 10:48 AM

Hi Reason, just finished listening to your Q&A with the Foresight Institute and found it really interesting! Any chance you would consider sharing or posting the Longevity challenges document mentioned in the Q&A? Would love to read something like that that could give a good idea of things to keep an eye on.

Thanks for everything you do!

Posted by: Matt at December 18th, 2021 6:32 PM

Off-topic: Q to the smart here. Could future engineered humans live as long as the oldest trees 5000y?

Posted by: Gekki at December 19th, 2021 3:45 PM

Not the smartest here but still will try to answer.

If a creature doesn't age, and doesn't accrue any new damage, which cannot be repaired, the lifespan is limited only by accidents, murder and such.

And ​with enough medical advances even our today's bodies could be kept alive indefinitely.

If we don't put a specific date or timeframe, eventually it well be possible, barring human extinction. Of course it might be many hundreds of years from now. I think it could be possible by the end of the current century.

I don't think we will ever need to engineer a body that can repair perfectly without any external technology. Might be done for some adventure or esthetic reasons. However, we are so dependant on the technology now that having a few more doesn't change that much.

There's a debate that afters some progress and some time the humans might decide to transcend the limitations of the human body and either merge with machines or even completely change the brain substrate. In this case there might be no "human" left. This path looks scary and is incomprehensible to us. The other path of never aging and keeping our bodies is almost business as usual , except we get rid of a fundamental human defect.

Posted by: Cuberat at December 19th, 2021 8:56 PM

Regrettably, big pharma and the medical industrial complex has so damaged their reputation during COVID-19, that it will require a complete reformation for me and many others to trust an injection created and offered by them. I suspect that if truth and reconciliation does not begin soon, that medical tourism may be the only safe recourse.

Posted by: Thomas Mark Schaefer at December 20th, 2021 10:25 AM
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