Considering the Near Future of Senotherapeutics

Senescent cells accumulate with age, and this accumulation drives a sizable fraction of the dysfunction of degenerative aging. While never present in very large numbers, these cells energetically secrete signal molecules that provoke inflammation and tissue remodeling. As noted here, a major theme in the development of senotherapeutic drugs to either selectively destroy senescent cells or broadly suppress the disruptive signaling of senescent cells is the need for greater understanding of the diversity of cellular senescence. Different tissues, different cell types, different origins of the senescent state may all be meaningfully different in their responses to drugs targeting one or another of the mechanisms identified to be important in cellular senescence. While early senolytic drugs are quite impressive in the benefits they produce in aged mice, later therapies produced in an environment of greater understanding will be better.

During the first senotherapeutics conference organized by the Phaedon Institute at the Buck Institute for Research on Aging, experts on the molecular and cellular mechanisms of aging, pathogenesis of age-related diseases, and drug discovery and development convened to delve into ideas on the past, present, and future of targeting senescent cells. A focal point of discussion revolved around the heterogeneity of cellular senescence, and its profound implications for the development of treatments. Presenters highlighted the diverse profiles of senescent cells, emphasizing differences in gene expression, secretory patterns, and functional roles, in addition to the importance of the tissue microenvironment.

Senescent cells represent a potential target for geroprotection and reduction of multimorbidity, but owing to current regulations, clinicians and pharmaceutical companies are focusing on the use of senotherapeutics for specific and selective age-related diseases. A Phase 2B trial sponsored by Unity Biotechnology is currently ongoing for the treatment of Diabetic Macular Edema (DME) using the senolytic agent UBX1325, which inhibits Bcl-XL. The Translational Geroscience Network runs a number of Phase 1 and Phase 2 trials using senolytic compounds, such as Dasatinib, Quercetin, and Fisetin, for the treatment of sepsis, chronic kidney disease, lung fibrosis, and Alzheimer's disease. Additionally, many other pathological conditions have been discussed as potential indications for the use of therapeutic compounds. For example, efforts are currently being made to selectively target senescent cell subtypes in pre-clinical models of skin and muscle dysfunctions with novel senolytic small molecules in development at Rubedo Life Sciences and Boehringer-Ingelheim, respectively.

While these represent pioneering studies and the opportunity to demonstrate the unequivocal pathological role of certain senescence subsets, challenges remain in the path to harnessing the therapeutic potential of targeting cellular senescence. Participants emphasized the need for a more comprehensive understanding of the dynamic nature of senescent cells, their role and localization in various tissues and tissue areas, and the need for more accurate and sensitive biomarkers. This discussion highlighted the importance of multi-laboratory and multi-center efforts in adapting the newest technologies with single-cell resolution for the identification and specification of senescent cells in vivo. These studies can offer novel targets for interventions and novel markers for a standardized evaluation of the efficacy of anti-senescence approaches in humans. Overall, the pleiotropic diversity and heterogeneity of cellular senescence invites the development of diverse strategies and modalities to target subsets of senescent cells according to their physiopathological roles. The ongoing effort in academic and industrial laboratories to develop different senotherapeutics is strategic to enable advancement in the clinic of multiple novel therapeutic opportunities, possibly in parallel.



Realistically, how many years before effective treatments get to the clinic? Senolytics have been around for well over a decade and we only have very small, limited, ongoing phase 1 and 2 trials. Why aren't there any news from the medical tourisim community? I can't imagine that people wouldn't have tried the D&Q combo. With this snail pace, age reversal won't get here in time for today's children.

Posted by: Barbara T. at February 13th, 2024 12:33 PM

@Barbara - I'm no expert, but I'll have a crack at answering your question.

I don't think there is much testing of D+Q because dasatinib is off patent. So a large trial costing tens of millions would probably bring a private company no benefits. Small non profit academic tests are probably all we can hope for.

I don't think there is a market for overseas senolytics for two reasons. The only easy to produce/obtain senolytic with some data is dasatinib + quercetin, and that can be obtained via mail, so there will never be much of a market for it at pricey overseas clinics. More expensive treatments like Senolytic CAR T cells currently cost half a million per dose to produce. Which is out of the price range of overseas clinics (and most healthcare systems).

The article I linked to in my previous comment showed that by sticking a T cell Lymphoma canner gene under the control of the chimeric receptor, pre conditioning with chemotherapy to "make room" for the CAR T cells to expand was no longer necessary, and the initial dose of T cells needed was hundreds to thousands of times smaller. Combine this with a gene therapy to produce the T cells in the body and you might have something (a gene therapy) that an overseas clinic could handle.

You'd probably still need some compelling data from a larger human trial paid for at great expense by a private company before you could start selling your overseas treatment though.

How could small overseas clinics fund some clinical trials to get data? Maybe this model could work one day:

Posted by: jimofoz at February 14th, 2024 5:10 AM

Hi Barbara,

Had a big comment eaten by the spam filter. But overseas clinics need something that is not a small molecule drug like dasatinib + quercetin, as people can just mail order that from India, but also not so expensive and difficult to make as CAR T therapies. Gene therapies may be getting cheap and effective enough to hit this sweet spot soon.

An injection of a gene therapy to make CAR T cells against senescent cells might happen overseas.

Posted by: jimofoz at February 15th, 2024 4:50 AM

Thanks for your answer. It seems like it did make it through the spam filter eventually. And it makes total sense.

Posted by: Barbara T. at February 20th, 2024 7:44 PM
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