A Cautious View of the Benefits of Senolytic Therapies

Senolytic therapies to selectively destroy senescent cells in old tissues have produced rapid rejuvenation in mice, turning back many different age-related diseases in many different studies. Senescent cells actively maintain a disrupted, inflammatory state of tissue when not cleared effectively by the immune system. Initial human trials of the dasatinib and quercetin combination (readily available to self-experimenters as well, prescribed off-label) have produced promising results. But as the authors of this paper note, there is still far too little human data to satisfy the cautions of regulators. Many more trials should be underway, particularly for dasatinib and quercetin, to definitively establish that this is a path worth pursuing, and allow the physician community to prescribe senolytics widely in the aged population.

Over the past decade, it has become clear that tissue ageing is caused by the accumulation of senescent cells, which alters the physiological responses in the surrounding microenvironment in an autocrine and paracrine fashion through the senescence-associated secretory phenotype (SASP). The body of evidence showing that elimination of senescent cells seemed to be largely beneficial led to huge research efforts to identify novel agents that eliminate senescent cells in humans. However, the repurposing of existing drugs and the use of new senotherapeutics are associated with various side-effects; incomplete functional characterisation of peripheral tissues at systemic administration; an absence of standardised guidelines for timing, dose, and route of administration; and a paucity of efficacy and safety data from clinical trials. Therefore, the full potential of senotherapeutics has been hampered in clinical applications.

It is likely that the best senotherapeutic against age-associated diseases and malignancies is yet to be discovered. Dasatinib, quercetin, and other senolytics were discovered using a mechanism-based approach. High throughput screening technology, which allows for automated testing of thousands of molecules present in chemical compound libraries in in-vitro senescence models, could assist with the discovery of new effective senolytics. To date, high throughput screening of commercial chemical compound libraries has led to the discovery of new families of senolytics: HSP90 inhibitors,the BET family protein degraders, and cardiac glycosides.

Furthermore, the safety and potency of existing senolytics can be improved by molecular engineering and drug delivery approaches. For example, the use of ABT263 is limited due to dose-limiting platelet toxicity. Researchers devised a proteolysis-targeting chimera technology to reduce the platelet toxicity of ABT263 by converting it into PZ15227. Compared with ABT263, PZ15227 was shown to be less toxic to platelets, but was a more potent senolytic in vitro and in vivo. Similar strategies might be useful to improve the efficacy and the safety profile of other toxic or repurposed senolytic agents.

In conclusion, senolytic drugs have shown promising results in the elimination of senescent cells and in alleviating various diseases in animal models. However, in patients, there is a paucity in data on the efficacy and safety of senotherapeutics from clinical trials, including systemic effects and side-effects. In this regard it is important to assess the specificity of senolytics in killing targeted senescent cells and their cytotoxic effects, to identify reliable markers for intervention responses, to elucidate interactions with comorbidities and other drugs, and to standardise administration protocols.

Link: https://doi.org/10.1016/S2666-7568(21)00300-7


'...the dasatinib and quercetin combination (readily available to self-experimenters as well, prescribed off-label)...'

Idk, where I live NO medical practioner will prescribe a chemotherapy drug for self-experimentation.
In my experience the same is true for ANY other prescription drug.

Posted by: Jones at January 19th, 2022 6:40 AM

nevertheless the medicine is available by some side channels. Either by playing with different jurisdictions or by contacting the supply chain. One problem with dasatinib is that it is relatively expensive , hence less available.

However, what annoys me is D+Q is generation I senolytic . What I want is a conjugated pro-drug with much better safety because it is better targeted. This one you cannot just find in a pharmacy even with a prescription.

Anyway, for now we don't have human data. Self-experimentation is done at amateur levels with varying degree of reliability and noise. If you can wait a few more years to see the result of humans trials that might be the best approach.

Posted by: Cuberat at January 19th, 2022 8:59 AM

'...with varying degree of reliability and noise.''
Same is true for the pro-league, though. So many studies can't be reproduced or lack the necessary info for reproduction, have wrong statistics, butchered P values, etc.
For almost everything claimed by a study you can find 2 which claim the opposite or something else entirely.
And most labs do shoddy work. Let them process the same sample twice with the same 5 or so parameters and chances are high that you will get quite different results. Gets even worse if you send the same sample to 2 different Labs.

Posted by: Jones at January 19th, 2022 9:15 AM

I think we would be much better off getting fisetin signed off first, it has a much better safety profile and it's readily available for a much cheaper price.

Posted by: Corbin at January 19th, 2022 10:43 AM

for all the deserved critique the studies and labs can receive the self experimenters are even less scientific. For startes, I cannot even guarantee that the fisetin i am taking is really fisetin. Then I have no idea what is the bio-availability and the effects are very subjective.

I would say that a big part of F being safe comes from the fact that it has very low water and alcohol solubility . It is very hard to overdose when your bio-availability is a joke. Also if something is effective it has side effects too. The less side effects usually means less primary effect. And senolytics have to be to some degree toxic. Ideally they should target some pathways which help the ScC to survive. However, the very same pathways also help the "good" cells do the normal repairs.

Posted by: Cuberat at January 19th, 2022 4:39 PM

Fisetin absorption is increased significantly with concurrent dosing of piperlongumine.

Posted by: JLH at January 19th, 2022 5:11 PM

@Cuberat wogonin, fisetin and kaempferol are among those few substances that change the color of the male sperm. So if you are a male you could easily detect the fake... even more, you can roughly differentiate which method of delivery does it with the smallest dose.

Posted by: SilverSeeker at January 20th, 2022 6:30 AM

@silver seeker, I have taken giga doses of both F and Kae, not together, I have not noticed any change in sperm color.

@JLH, seems improbable. What is the source on that solubility claim?

Posted by: JohnD at January 20th, 2022 11:12 AM

@JohnD with fisetin it starts visibly at around 500-600 mg. How do you take fisetin? What emulsifier and/or solvent do you use?

Posted by: SilverSeeker at January 21st, 2022 9:22 AM

At SS. I take 2,000 mg when I take it. Have done so 4 times. Doctors Best brand. I don't take any emulsifier or solvent. Taken on empty stomach

Posted by: JohnD at January 21st, 2022 8:18 PM

@JohnD I've taken Swanson, Doctor's Best, RevGenetics (depending on current availability and price promotions) brands and one no name imported through local small supplement maker directly from China, and all have the same effect when taken with buttermilk. Taken with water only on empty stomach none of them has this effect as fisetin is almost completely insoluble in water.

Posted by: SilverSeeker at January 24th, 2022 6:18 AM

so what is the best protocol and solvent according the hm.. handsdown approach ?

Posted by: Cuberat at January 24th, 2022 5:10 PM

@Cuberat prevention by telomere elongation.

Posted by: SilverSeeker at January 25th, 2022 10:35 AM
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