Improving on Fisetin as a Senolytic

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.

Comments

some people can experiment on themselves with fisetin and other non-patentable products/services.
so, if there are two identical twins {genetically the same}. one twin can swallow a dose of fisetin and the other twin can swallow a placebo pill and after a few months a researcher can compare senescent cells burden of both twins and publish the results on internet -- free and open public access.

Posted by: nicholas D. at November 5th, 2024 5:34 PM

Here is my protocol:

I do every third month a three days water only fast. Autophagy is at it's peak between 24 - 48 hours then it declines. On the third day I dissolve the content of 15 capsules of Fisetin ( 1500 mg ) in a tablespoon of olive oil.

Any thoughts?

Posted by: Stephan at November 5th, 2024 7:38 PM

Normal bioabsorption of fisetin is not very good.It is not really water soluble. Adding an oil or a fat, eg butter, is a good idea.
Alcohol also improves bioavailability so take in the evening with a fine cheese and a decent glass of red.

No reason why it should not be every day.

Posted by: JLH at November 6th, 2024 4:28 AM

A recent pre-publication: ([2024] Rejuvenation driven reprograming in T lymphocytes.pdf) has demonstrated that using a small peptide derived from sestrin-2, can disrupt the signaling cascaded between sestrin>AMPK>MAPK. These disruptors of sestrin (DOS) target the stress induced signaling cascade between sestrin-MAPK complexes (sMAC) in immune cells, specifically those accumulating in aged or senescent cells, This intervention demonstrated significant rejuvenation of senescent cells in mouse models. The ability to revive and improve as opposed to killing and clearing has dramatic benefits over senolytics.

• Rejuvenated T cells: DOS converts senescent T cells into stem-like, long-lived memory T cells, expanding immune surveillance and functionality.
• Enhanced antigen response: DOS-treated T cells undergo de novo TCR rearrangements, enabling them to respond to previously unencountered pathogens.
• Robust antiviral immunity: Treated aged mice showed strong immune responses and high survival rates in lethal viral challenges, even without prior vaccination.
• Reversal of senescence markers: DOS reduces cellular aging markers, such as β-galactosidase and DNA damage foci, enhancing overall cell fitness.
• Increased cell proliferation: DOS restores youthful proliferation in senescent T cells, supporting sustained immune responses and regeneration.
• Maintenance of telomere length: DOS prevents telomere shortening, preserving immune cell functionality over the long term.
• Sustained T cell function across organs: DOS maintains T cell functionality in key immune organs (lymph nodes, thymus, spleen), essential for effective immune responses.

A greatdeal of informaion is available on following webpage: "Disruptors of the Sestrin AMPK/MAPK Complexes," https://www.age-regression.com/dos-smacs2. The full text of the paper can be found here: https://www.researchgate.net/publication/384821561_Rejuvenation_driven_reprograming_in_T_lymphocytes

Posted by: Michael Slattery at November 6th, 2024 10:18 AM
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