The Forever Healthy Foundation Knowledge Base on Dasatinib and Quercetin as a Senolytic Therapy

The Forever Healthy Foundation has been building a database of materials covering presently available options for the treatment of aging, all of which have little available data in comparison to more established areas of medicine. The bias in these materials is towards a very conservative viewpoint, appropriate for physicians, so you will see little to no enthusiasm for forging ahead with use, as the self-experimenters in the longevity community are presently doing. Nonetheless, this provides a convenient repository of information, pulling together references to all of the animal and human data available for the topics under discussion.

The latest article covers the senolytic combination of dasatinib and quercetin, currently in human trials, and with more and better data to back it up than most other approaches. The effects in mice are eye-opening in comparison to anything else yet tried in the field of rejuvenation; quite rapid reversal of many age-related diseases and measures of age-related degeneration. Dasatinib is a chemotherapeutic, and when used continuously produces the usual range of unpleasant, toxic outcomes. When used only very intermittently, as a senolytic, the situation is very different. Still, as pointed out here, there is little data in humans, if one is to be conservative.

Dasatinib and Quercetin Senolytic Therapy

Clinical data on the possible benefits and risks of using dasatinib and quercetin (D+Q) as senolytics is extremely limited. Published results exist from 3 human trials, two in diseased populations and one in healthy subjects. A total of only 8 benefits were documented in these clinical studies. Of the 8 benefits, 5 were actually various measurements of markers of senescence or the SASP, hypothesized to translate to clinically beneficial effects. Only 3 benefits had any direct clinical relevance and they were of low magnitude. Based on the current state of evidence, the beneficial effects of D+Q seem to be extremely limited in humans.

Several more benefits that encompass many organ systems have been reported in preclinical studies. However, the amount of relevant preclinical research is also limited. We identified only 31 preclinical trials related to D+Q as senolytics and the majority of reported benefits occurred exclusively in diseased animals. Only 13 trials included a group of "healthy" animals that were treated with D+Q. Of those 13 trials, only 6 reported a positive effect of D+Q senolytic treatment on aged, otherwise healthy animals as compared to controls.

The main benefits seen in clinical and preclinical trials of D+Q senolytic therapy are: (a) decreased markers of senescent cells in various tissues (clinical and preclinical); (b) increased health span and lifespan (preclinical); (c) improved cognition and cortical blood flow (preclinical); (d) decreased amounts of liver fat (preclinical); (e) improved vasomotor/endothelial function (preclinical); (e) decreased intimal plaque calcification (preclinical). The main risks that have appeared in clinical trials are mostly due to dasatinib. In the two high quality, open-label human pilot senolytic trials there was only one serious adverse event reported (bacterial multifocal pneumonia and pulmonary edema superimposed on the idiopathic pulmonary fibrosis that was the subject of the trial) and no subjects required drug discontinuation.

The 3 clinical trials published to date have all used different protocols (doses, frequency, duration, and repetition). There is no consensus on the optimal treatment protocol. Unfortunately, as of today, there is no single test that is completely sensitive or specific for senescent cells. Generally, a combination of assays is needed to estimate the senescent cell burden in tissue samples. It is unknown if senescent cell abundance in biopsies of skin, adipose tissue, or other tissues, cheek swabs, cells in blood reliably reflect senescent cell abundance overall. Similarly, whether levels of SASP factors or senescence-associated microRNAs in plasma or blood cells reflect senescent cell burden is not clear.

Therefore, until there are more published results showing benefits in humans, a clearer picture of the senolytic-use specific risk profile, and a consensus on the treatment protocol, we will avoid the use of D+Q senolytic therapy.

Comments

What about human studies with secong generation senolytics like prodrug conjugated navitoclax or dastatinib?

Posted by: Cuberat at June 24th, 2021 5:03 PM

@Cuberat Second generation senolytics are tested by Unity, Oisin, etc... We won't get interesting human data (phase 2 trials) before 2025. Molecules already on the market which are repurposed as senolytics are considered 1st generation senolytics.

Posted by: Jonathan Weaver at June 25th, 2021 4:03 AM

I wouldn't hold my breath for Unity's senolytics results. According to their current pipeline (https://unitybiotechnology.com/pipeline/) they have only a single compound listed with 'Senolytics' as mechanism. That compound is in phase 'lead optimization' 2 steps away from a phase 1 trial.
They'll run out of money before they even get there.

Posted by: Jones at June 25th, 2021 6:36 AM

@jonathan - Can you name any 1st generation sexol├│gicos available now? I'd to try getting them.
Thanks

Posted by: Joe Da Silva at June 25th, 2021 5:57 PM

*senolytics

Posted by: JoeDa Silva at June 26th, 2021 1:15 PM
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