The enormous cost of medical regulation ensures that natural compounds that may be useful receive little rigorous attention in the form of clinical trials and correspondingly little adoption in the mainstream medical community. Since the use of these compounds cannot be patented in a way that prevents competition, companies focused on these compounds cannot become valuable enough to raise the funding needed to conduct extensive development and formal clinical trials. Thus little tends to be known in certain about even quite widely used natural compounds, far less than is known about the average small molecule drug.
We can see these incentives at work in the case of the senolytic flavonoid fisetin; despite the existence of animal data suggesting it to be as good at clearing senescent cells from aged tissues as the combination of dasatinib and quercetin, we still don’t know if it works in the same way in humans, what the optimal dose might be, how delivery is best improved given its low bioavailability, and so forth. No-one is putting significant funds into answering any of those questions, and it is unlikely that anyone ever will. What does tend to happen, as illustrated by today’s open access research, is that groups attempt the slow process of producing patentable variants of the molecule in question and move ahead with those into the regulatory system.
Development of novel flavonoid senolytics through phenotypic drug screening and drug design
Accumulation of senescent cells drives aging and age-related diseases. Senolytics, which selectively kill senescent cells, offer a promising approach for treating many age-related diseases. Using a senescent cell-based phenotypic drug discovery approach that combines drug screening and drug design, we developed two novel flavonoid senolytics, SR29384 and SR31133, derived from the senolytic fisetin. These compounds demonstrated enhanced senolytic activities, effectively eliminating multiple senescent cell types, reducing tissue senescence in vivo, and extending healthspan in a mouse model of accelerated aging.
Mechanistic studies utilizing RNA-Seq, machine learning, network pharmacology, and computational simulation suggest that these novel flavonoid senolytics target PARP1, BCL-xL, and CDK2 to induce selective senescent cell death. This phenotype-based discovery of novel flavonoid senolytics, coupled with mechanistic insights, represents a key advancement in developing next-generation senolyticss with potential clinical applications in treating aging and age-related diseases.
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