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Fisetin: Senolytic!

fisetin senolytic

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#1051 ambivalent

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Posted 20 February 2022 - 12:25 PM

Back to fisetin: My father has just been diagnosed as pre-diabetic; I don't recall fisetin being mentioned too much here in relation to diabetes (though its been a loing thread). There appears to be some interesting research:

 

Both from 2011

 

https://www.salk.edu...stem-disorders/

 

"This manuscript describes for the first time a drug that prevents both kidney and brain complications in a type 1 diabetes mouse model,” 

 

 

https://www.hindawi....am/2012/639469/

 

"Understanding these mechanisms will be critical towards establishment of fisetin as a natural therapeutic agent for the treatment of chronic inflammation associated with diabetes and its complications."

 

 

 


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#1052 Telo

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Posted 08 March 2022 - 04:40 PM

If you take 400 or 800 mg Fisetin per day for five days/month, how much would that interfere with the effect of blood thinners? (it's for my father) I know, he should talk to his doctor, but his doctor probably will have little knowledge about senolytics... Maybe he could start with smaller doses, see what the blood tests show and then gradually increasing.

 



#1053 Harkijn

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Posted 08 May 2022 - 02:12 PM

In case you missed it:

 


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#1054 Mind

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Posted 08 May 2022 - 05:47 PM

In case you missed it:

 

 

I see in the comments section that people wondering about the administration of the Fisetin in the ITP program and whether or not they did mass spec on the the blood samples.


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#1055 ambivalent

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Posted 25 August 2022 - 03:51 PM

Around 18 months ago my mother fell and fractured her shoulder, also injuring a knee. She had, she recently informed me, still retained fluid on the injured knee. On a few occasions she has taken fisetin protocol - a gram a day for three days - but never in the form I preferred she take: with a mixture of lecithin and olive oil. This time, a couple of weeks back, on the third day she did. Two days later or so she noticed the effusion had mostly disappeared. Any thoughts as to why a dose of fisetin would cause this?



#1056 ambivalent

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Posted 27 August 2022 - 03:37 PM

Well, the dormancy of this thread lays my embarrassment bare as the post, my post, heading this page references fisetin being possible as a "natural therapeutic agent for the treatment of chronic inflammation associated with diabetes and its complications" and so more than hints at the role fisetn appears to have played in alleviating an 18 month knee effusion condition for a 75 year old woman.

 

Looking around:

 

Targeting pro-inflammatory cytokines following joint injury

 

https://arthritis-re.../10.1186/ar4591

 

Introuduction: "Post-traumatic arthritis (PTA) is a progressive, degenerative response to joint injury, such as articular fracture. The pro-inflammatory cytokines, interleukin 1(IL-1) and tumor necrosis factor alpha (TNF-α), are acutely elevated following joint injury and remain elevated for prolonged periods post-injury........"

 

And:

 

FIsetin inhibiting IL-1β in mouse model:

 

https://pubmed.ncbi....h.gov/28213268/

 

"The in vivo effect of fisetin was evaluated by gavage in mice OA models induced by destabilization of the medial meniscus (DMM). We found that fisetin inhibited IL-1β-induced expression of NO, PGE2, TNF-α, IL-6, COX-2, iNOS, MMP-3, MMP-13, ADAMTS-5. Besides, fisetin remarkably decreased IL-1β-induced degradation of Sox-9, aggrecan and collagen-II. Furthermore, fisetin significantly inhibited IL-1β-induced SIRT1 decrease and inactivation. However, the inhibitory effect of fisetin was obvious abolished by sirtinol, suggesting that fisetin exerts anti-inflammatory effects through activating SIRT1. In vivo, fisetin-treated mice exhibited less cartilage destruction and lower OARSI scores. Moreover, fisetin reduced subchondral bone plate thickness and alleviated synovitis. Taken together, these findings indicate that fisetin may be a potential agent in the treatment of OA."

 

 

https://www.nature.c...598-021-87257-0

 

"Fisetin is a naturally occurring flavonoid that possesses several pharmacological benefits including anti-inflammatory activity. However, its precise anti-inflammatory mechanism is not clear. In the present study, we found that fisetin significantly inhibited the expression of proinflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2), and cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages."

 

 

Well, my own experience with fisetin was significant improvement in an arthritic knee, following an inititial worsening for a few days after a large dose, this happened each time with a periodic dose months apart, each time post protocol pain was less. I had initially put this down to the clearance of senescent cells, which it may well have been, but perhaps it was fisetins anti - inflammatory property. This I experienced overnight after months of quite severe histamine induced breathing diffilculties whch almost completely cleared up overnight, after the first dose.

 

Another observation, I would need to check how many 3 day protocols my mother had taken over the previous year, but it was several and this was the cycle that did it. As mentioned, she hadn't prior taken it in such a neat bioavailable mixture: olive oil + lecithin + fisetin. She most likely won't again unfortunately as she found it extremely unpleasant, though she will now add it to yoghurt. 

 

Efforts to ensure bioavaialbility seem to be important and to date we appear to have little, that I am aware, in human measurement on bioavailability, nor the effect of senescent cell removal in humans. 

 

 


Edited by ambivalent, 27 August 2022 - 03:56 PM.

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#1057 ambivalent

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Posted 22 September 2022 - 05:25 PM

The other day I looked back at an entry posted a couple of months after my first rather miraculous and large fisetin dose of three grams mixed in olive oil. I had been suffering for months with an allergic chronic cough, likely histamine induced. Eventually, went to the doctors and was immediately admitted, quite a feat in the UK, dispensed anti-histamines and inhalers which offered some relief, but not solving the problem. Three grams mixed with olive oil and it was an overnight success - though confounded with taurine and NMN, but these would only likely have been causative synergistically. Anyhow, it was subsequently pointed out in the thread that fisetin suppresses mast cell activation

 

I'd forgotten, though, that the waking apnea went too, and red wine had stopped making me cough, which it had done regularly for at least 15 years. It may have occurred since but not so that it has been recollected. 

 
I had noticed too over the last couple of years not experiencing too much trouble with candida. This was especially surprising since although I have taken coconut oil and caprylic acid acid from time to time, I hadn't done so prolonged or intensely. Poor diet and alcohol intake has increased signifcantly over the past couple of years, with next to no fasting, yet there has been no signifcant resurgence. So I wondered, perhaps if fisetin had something to do with it. 
 
Well, I found a couple of studies linking candida to poor outcomes in obstructive sleep apnea (I used to have a problem here too and, noting the study, poor dental health) and COPD mortality and reccurrence
 
Is there a link between candida and mast cell activation?   
 
Well, 
 
https://www.ncbi.nlm...les/PMC5812373/
 
"Overall, these studies indicate that mast cells can influence innate immune responses against bacterial and fungal infections via multiple mechanisms. Importantly, the contribution of mast cells to infection outcomes depends in part on the infection model, including the genetic approach used to assess the influence of mast cells on host immunity, hence highlighting the complexity of mast cell biology in the context of innate immune responses.

 
As for the red wine, it has been recommended to avoid alcohol while trying to eliminate candida, though I haven't been able to find something substantial and specific to the red.
  
The following post-fisetin day with the coughing 90% abated, I decided to test for said vin rouge, which always set it off. The inebriation was cough-free and cannot recall an incident since, there has perhaps been the occasional sign of candida and the kind of brain fog I used to experience seems to have staved off considerably. But I supplemement intermittently more with zinc, magnesium and iron now, while the former has been shown to regulate histamine.  One interesting study, and I appreciate this probably needs its own thread, but since it is quiet, shows that when deprived of zinc the candida cells become stressed and form goliath cells. ZInc is dumped in order to fight off the infection, so supplementing, one assumes would be a bad idea with candida overgrowth, though initially perhaps it might make our zinc depleted selves feel good.

 

Anyhow, on to the interesting stuff - this a fabulous entry on the anti-fungal mechanisms of flavanoids. The flavanoid modes of fungal attack are quite impressive:

  • Inhibition of efflux pumps - Efflux pumps are transporters present in most living cells, including fungi; they have the noteworthy function of removing toxic substances from the fungal body. This transporter can detoxify a fungal cell through the removal of a drug being accumulated. The high efflux pump’s expression can lead to drug-resistance. Hence, inhibiting the efflux pumps is a crucial aim for reducing drug resistance.
  • Inhibition of cell division - The inhibition of cell division generally causes inhibition of microtubule polymerization, which inhibits the mitotic spindle formation.
  • Inhibition of RNA/DNA division or protean synthesis - The antifungal agent generally enters into the cell through active transport that reaches into the nucleus, and thus inhibits DNA, RNA, and protein synthesis. The inhibition of protein synthesis is well-recognized as an antifungal target............ Carvacrol, a chalcone extracted from Lavandula multifida L. that inhibits the nucleic acid synthesis and disrupts the cellular cytoplasmic membrane, eventually causes apoptosis in various candida species
  • Plasma membran disruption - The ergosterols are a vital component for the manufacturing of cell membranes. Antifungal drugs normally inhibit the ergosterol biosynthesis, and the cell membrane’s integrity is perhaps disrupted, leading to leakage of intracellular components. This inadequate formation or disruption of the plasma membrane leads to a lesion or membrane permeability changes 
  • Mitochondrial disfunction - Inhibition of the mitochondrial electron transport chain (ETC) leads to diminishing membrane potential. This inhibition generally takes place in the ETC by inhibition of proton pumps, which reduces ATP synthesis, and thus, cell death......quercetin, resveratrol, and curcumin modulate mitochondrial functions by inhibiting oxidative phosphorylation through various mitochondrial enzymes, or by changing the generation of ROS in mitochondria and by modulating the activity of transcription factors which control mitochondrial proteins’ expression. All these compounds exhibit pro-apoptotic functions, mediated by the ability to discharge of cytochrome c from mitochondria, or indirectly by upregulating pro-apoptotic proteins of Bcl-2 expressions and downregulating anti-apoptotic proteins
  • Inhibition of cell wall formation - The cell walls of fungi are primarily composed of β-glucans and chitin. The antifungal mechanism has been based on cell wall deformation which is caused by the inhibition of the synthesis of those compounds....... The antifungal process is achieved based on the cell wall deformation which includes the remarkable decreasing of cell size and increasing membrane permeability. Similarly, glabridin treatment enhances the expression of various genes in C. glabrata which participate in the fragmentation of DNA (chromatin condensation) resulting in apoptosis.

 

So I am rather forced to conclude, that the high dose of fisetin likely killed off candida overgrowth, which in turn was causing a chronic hsitamine response and many zinc deficiency symptoms I appear to have developed over the years.

 

Fisetin, quercitin and curcumin are three flavanoids which we know to be senolytics and so the sciency lay question that follows in light of reading the flavanoids' impressive antifungal assault range is, are some, any of these, the potential mechanisms through which fisetin et al act as a senolytic? Are the flavanoid senolytic mechanisms known? It would seem pretty likely, Unity's DME drug, for example, removes sensescent cells through blocking proteins.  It would make sense that some of the mechanisms known to attack fungus, would be triggering apoptosis in sensecent cells - given it is already known some flavanoids are deleterious to those cells.

 

It would seem too reasonable to assume those mechanisms that would work against senescent cells can be used synergistically with other compounds/drugs - I'm assuming the inhibiting cell division line of attack would be one to rule out !  It might seem quite reasonable, I'd have thought, that some of these flavanoids which may not be effective at triggering apoptosis on their own, could be used in combination with other flavanoids or drugs. There would seem to be considerable grounds for experimentation with the flavanoids. If I recall correctly Dastanib + Quercitin were shown to be synergistic. 

 

 

 

 

nb I did experience significant candida symptoms with the Turnbuckle's Alzheimers Protocol, which should be done with real care, with the likely breaking up of candida plaques, which may have contributed to some of the remission; however, the symptom relief from fisetin was instantaneous and independent.    


Edited by ambivalent, 22 September 2022 - 06:21 PM.

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#1058 ambivalent

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Posted 24 September 2022 - 01:51 PM

I see in the comments section that people wondering about the administration of the Fisetin in the ITP program and whether or not they did mass spec on the the blood samples.

 

An additional query I have is the mechanism through which senescent cells are turned apoptopic - which presumably is the senolytic challenge. Both seem dependent on telmomere length, although it doesn't seem clear whether it is causative or corrleative from the literature. 

 

Apparently once one telmoere reaches a certain length, the whole cell turns senolytic regardless of the lengths or average of others:

 

https://pubmed.ncbi....h.gov/11595186/

 

which I caught from this paper:

 

https://www.ncbi.nlm...les/PMC4761709/

 

There does seem a suggestion that senescence can be induced through other markers, presumably without the need for short telomeres. Telomere length too is a marker for apoptosis. 

 

But what is the causative or interactive relationship between telomere length and cell apoptosis and sensescence. Could it be that certain enzyme expression, say, sees the cell move to apoptosis and another to senescence conditioned by some telomere length? And how to move from senescence to apoptosis. And might there be some function of telomere length or cirtical number of telomeres which trigger apoptosis, say, since presumably the telomere lengths are frozen once senescence starts. 

 

The reason for these related questions is whether or not telomere length might play a role the responses of inbred and diverse mice to clearance of senescent cells with fisetin.

 

Below a (2000) paper on mice telomere length

 

https://www.ncbi.nlm...have,11,14–16).

 

"Established inbred mouse strains have long, hypervariable telomere lengths, ranging from 30 to 150 kb. In contrast, the wild-derived mouse species Mus spretus, has telomeres ranging from 8 to 10 kb."

 

In general it seems from other species :text=Using%20genomic%20measures%20of%20inbreeding,telomeres%20(n%20%3D%201195).' class='bbc_url' title='External link' rel='nofollow external'>passerine, house sparrow inbreeding shortens telomeres.

 

"Interestingly, our data suggests that, not only are long telomeres not conserved among mouse species, but that most mouse species studied have short telomeres. These differences in telomere length do not likely represent strain-specific requirements for telomere length, because closely related strains of M.musculus show very different TRF distributions. Additionally, we found no correlation between telomere length and longevity in closely related mouse strains. In fact, the strain with the shortest telomeres of those we studied, P.leucopus, had the longest lifespan."

 

This doesn't seem to be too reliable since in this invitro study DMSO - demonstrated to have been apoptotic under certain conditions - was used would be a little concerning too if not just targetting sensecent cells. 

 

https://www.ncbi.nlm...om=groupmessage

 

"Chronic fisetin treatment of HF at physiological concentrations resulted in shorter telomeres compared to control cells, indicating reduced telomere stability and enhanced biological aging of these cells." 

 

"However, under conditions of chronic oxidative stress, both fisetin and minocycline appeared to reduce the rate of telomere shortening."

 

So if it is the case, albeit a stretch, that fisetin causes a shortening of telomere length in vivo and this is the mechanism through which it induces apoptosis in sensecent cells, then might significantly different telomere lengths in mouse species play a role in senolytic efficacy?   


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#1059 ambivalent

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Posted 24 September 2022 - 02:02 PM

Fisetin induces apoptosis in colon cancer cells by inhibiting a number of signalling pathways:

 

https://www.ncbi.nlm...cles/PMC2722149

 

"We suggest that fisetin could be a useful agent for prevention and treatment of colon cancer."


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#1060 ambivalent

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Posted 25 September 2022 - 01:42 PM

I have just noticed the link to the much hyped and anticipated 'fabulous entry on the anti-fungal mechanisms of flavanoids' in the above post didn't work. So here it is:

 

https://encyclopedia.pub/entry/10699


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#1061 ambivalent

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Posted 29 September 2022 - 01:32 PM

This has become something of a fisetin catch-all thread, so I though it best to locate the latest addition, of a clinical trial, in a more appropriate forum than senolytics:

 

Fisetin Prolongs Therapy Window of Brain Ischemic Stroke Using Tissue Plasminogen Activator

 

 


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#1062 ambivalent

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Posted 30 September 2022 - 04:03 PM

Yesterday, I dosed fisetin for the first time in a couple of months. Six grams in olive oil. Well, I haven't noticed too much so far mostly minor anecdotes.

 

Compared to the first dose maybe four years ago, where there was considerable pain in an arthritic knee the day after, I have noticed none, perhaps slightly at the back, when bending. This was a consistent response to fisetin, albeit weaker each time, but there is still a window open for this weakness to express itself. I do seem to remember once, the knee unexpectedly just giving way rather alarmingly, but recovering almost immediately, which I believe was after a fisetin dose.  

 

The knee which has damaged ligaments from a 30 plus year injury is remarkably strong compared to 5 years ago - I noticed improvements through high dose Fisetin, NMN and the TBs stem cell protocol over the intervening period.

 

Yesterday I felt some discomfort, an ache, in the groin area where I had an operation 15 years ago, it has caused some problems over the years.

 

Memory was hazy and there seemed an increase in verbal errors.

 

Woke up today, not sleeping well, with a very mild achiness that would be associated with flu and have generally felt a little heavy headed.

 

Noticed today too, climbing some stairs that the calf muscles felt weaker.  

 

Some mild discomfort in the ribs which too, which I take to be an expression of old injuries - something I have associated with fasting.


Edited by ambivalent, 30 September 2022 - 04:27 PM.

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#1063 ambivalent

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Posted 30 September 2022 - 07:32 PM

Well, many of us no longer receive longecity emails, a few may have seen this fisetin mouse study turn up in a commercial email, which brings the thread back on the senolytic track:

 

Senolytic elimination of senescent macrophages restores muscle stem cell function in severely dystrophic muscle

 

There was no priming either, I read this after reporting the weakened muscles from a fisetin dose.

 

"We administrated fisetin to mdx/utro(−/−) mice for 4 weeks, and observed obviously reduced number of senescent immune cells, restored number of muscle cells, and improve muscle phenotypes. In conclusion, our results reveal that senescent immune cells, such as macrophages, are greatly involved in the development of muscle dystrophy by impacting the function of muscle stem cells, and the senolytic ablation of these senescent cells with fisetin can be an effective therapeutic strategy for improving function of muscle stem cells and phenotypes of dystrophic muscles."


Edited by ambivalent, 30 September 2022 - 07:32 PM.

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#1064 ambivalent

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Posted 04 October 2022 - 08:28 PM

Well, to add further I took quite a lot of a liposomal fisetin + quercitin of an unfamiliar brand on top of the 6 grams, I wouldn't have added too much except to say that I was pretty tired with headaches the following day. There would have been something reliable to report if I hadn't confounded it, though still interesting in itself. I mentioned weakening in the muscles a few days ago, well I have noticed a definite improvement in muscle tone over the last couple of days. But I don't exercise regularly to test this; however, today I climbed some steps up the side of a cliff this is usually pretty tiring, the weather has cooled somewhat making it easier, but I didn't notice it all until I was at the top and became aware of my lack of awareness of the climb. This makes sense with the above research, of fisetin improving muscle through the elimination of sensecent cells and is consistent with prior experiences of weakening then strengthening of problematic knee (though not muscular) with fisetin. 

 

The confounding factor, though, is c60. I hadn't taken any for at least a couple of months, opened a bottle and applied a little topically. Well, there was a coating on the finger which, was, well, ingested. And that amount probably could have an impact. I was cautious about using c60 while taking fisetin because, and I seem to recall reading this in a paper there was a relationship between ROS signalling and fisetin, though I can't recall the detail, and it has long been held that c60 was an ROS sponge.

 

Also, increased clarity too. 


Edited by ambivalent, 04 October 2022 - 08:39 PM.

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#1065 ambivalent

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Posted 31 October 2022 - 03:19 PM

I had been experimenting with this brand, referred too in the previous post,  which seems a little too good to be true price wise:

 

https://www.longecit...nolytic/page-36

 

A little misleading on the label, but 2 capsules one dose. So 30 grams of liposmal fisetin plus 6 grams of quercitin. Completed my second bottle, but not clean been taking C60 with it and intermittent dosing of NMN. Yesterday, took 22 capsules, that which was left, to see the effects Was expecting considerable brain fog today which I experienced a couple weeks back the day after a dose likely, to have been around half.

 

I had some very mild symptoms last night, glands were modestly up, felt sleepy early, then found it a little hard to sleep. Noted slight verbal errors, but felt fine today and pretty clear minded.

 

My sense is that these capsules have contributed to weight loss and better muscle tone.

 

On weight loss:

 

"In this study, we have demonstrated that fisetin prevents diet-induced obesity through regulation of the signaling of mammalian target of rapamycin complex 1 (mTORC1), a central mediator of cellular growth, cellular proliferation and lipid biosynthesis."

 


Edited by ambivalent, 31 October 2022 - 03:27 PM.

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#1066 ambivalent

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Posted 03 November 2022 - 03:50 PM

Well, if 22 then why not 60? Well, 59 there one escaped for a day before being recaptured - the missing link from the previous post. So that would be 29.5 grams of liposomal fisetin and 5.8 grams of liposomal quercitin. If it is as it says on the tin, which must be doubtful with supps and with one that seems so well priced. I downed probably superfluously with olive oil and not on an especially empty stomach - which shouldn't matter too much I'd assume with liposomal.

 

Nothing noticeable yesterday except restiless sleep and today I have a noticeable background headache. As mentioned I'd notice some changes with the an inchorent period of c60, fisetin and NMN. No NMN lately or for a while - I dosed a little c60 a couple of hours after the fisetin bottle-gulp. 

 

I have another and may try again tomorrow. In the past it can take a few days before some things become noticeable, so we'll see. But one would assume, that when it comes to senescent cells, there is a limited return on investment, though that is far from all what fisetin does. This is an experiment with "more" and wondering if more may encourage a deeper clearance, if that is a sensible analogy.

 

Probably the main concern I have is wound healing, and it is not a vulnerability signalled, until experienced - both myself and lost69 had some problems a year a back - my experience was of a transient vulnerable window, lost though was dosing high every day rather than intermittently as I was. 

 

This is of course unrationalised pure experimentation, and is being reported as such - it is probably 3 times outside of reported norms, that I am aware, and that wasn't iposomal iirc. 

 

This of course assumes that the levels reported are contained which is highly questionable with supps - so if I go with a different brand again, I would build up, rather than assume that this was a 30g experiment. 

 


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#1067 ambivalent

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Posted 05 November 2022 - 03:44 PM

Well, I doubled down. Two bottles in two days, which if it as reported, would be 60 gams of liposmal fisetin ans 12 grams of quercitin.

 

The background headache induced by the first didn't worsen when taking the second. I had a couple of glasses of wine on the second and third days, which would clouded measurement. 

 

I didn't feel much except rib pain which has become synonymous with fasting and fisetin - what I have always taken as repair from old injuries.

 

No trace of very modest flu like symptoms reported at recent lower doses, which may indicate sensecent cells have been largely cleared. Well, maybe. But, also I have purposefully taken with C60.

 

My curiosity is over the next couple of weeks, to see whether such a high doses have some delayed affects reported by some others.  

 

I had mixed in NMN, c60, and fiseting over a few weeks - NMN separately, and wanted to see if by ramping up fisetin it could be identify it as the cause.

 

I would tentatively suggest the muscle strengthening observed recently has weakened over the last couple of days which is a good sign, consistent with fasting naturally, where fasters often report muscle grows back stronger. Though, from at least a couple of years back, it hadn't been established senescent cells are cleared usring fasting, though empirical evidence would suggest it were the case.

 

As of writing, clarity seems improved too, which is consisent with reported effects of fisetin.  

 

   

 

 


Edited by ambivalent, 05 November 2022 - 04:35 PM.

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#1068 ambivalent

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Posted 08 November 2022 - 02:52 PM

This is pretty interesting, CMS121, a drug derived from FIsetin to treat Alzheimers and the phase 1 results are due around now:

 

https://www.technolo...-testing-354533

 

Also from that article:

 

https://www.salk.edu...ng-study-shows/

 

"“The contribution of old age-associated detrimental processes to the disease has been largely neglected in Alzheimer’s disease drug discovery,” says Antonio Currais, a Salk staff scientist and first author of the new paper.

 

Maher and David Schubert, the head of Salk’s Cellular Neurobiology Lab, previously developed CMS121 and J147, variants of plant compounds with medicinal properties. Both compounds tested positive for their ability to keep neurons alive when exposed to cellular forms of stress related to aging and Alzheimer’s disease. Since then, the researchers have used the drug candidates to treat Alzheimer’s in animal models of the disease. But experiments revealing exactly how the compounds work suggested that they were targeting molecular pathways also known to be important in longevity and aging.

 

In the new research, Maher, Currais and their colleagues turned to a strain of mice that ages unusually fast. A subset of these mice was given CMS121 or J147 beginning at nine months old—the equivalent of late middle age in humans. After four months, the team tested the memory and behavior of the animals and analyzed genetic and molecular markers in their brains.

 

Not only did the animals given either of the drug candidates perform better on memory tests than mice that hadn’t received any treatment, but their brains showed differences at the cellular and molecular levels. In particular, expression of genes associated with the cell’s energy-generating structures called mitochondria was preserved by CMS121 and J147 with aging.

 

“The bottom line was that these two compounds prevent molecular changes that are associated with aging,” says Maher."

 

 

I looked up J147 and it is a curcumin derived drug.  I wonder if we could expect real optimism at this drug, CMS121, being used for a range of neurological disorders given that pre-clinical studies have been shown to be beneficial across so many disorders:

 

https://www.ncbi.nlm...es/PMC7990461/#

 

I thought too I'd post this anecdote from reddit, where a guy showing apparently white hair turning grey, created a thread, which has been linked on this site before. He was then asked if he had noticed any mental effects and his response was as follows:

 

"Not really. But it's had a HUGE effect on my mother-in-law. She's been having alzheimers memory problems for years but in the last 2 she's had severe mood swings sometimes resulting in rage, paranoia and violent behavior - to the point in the last 6 months my father in law couldnt leave her at home alone.

 

She started taking 500mg daily and within two weeks her moods completely stabilized to the point where my FIL could go back to his usual 3-4 days/week golfing again.

 

It's one month later and my wife says her mothers memory has improved to the point she's not telling her the same thing over and over in the phone conversations they have during the week and that she sounds "totally normal now" on the phone.

 

It's third hand information filtered through my wife so take it with a grain of salt... I'm not in El Paso to directly observe my MIL. My FIL did say to my wife the fisetin is a 'miracle' drug for them. I get the impression he was so desperate he'd try almost anything."

 

 

 


Edited by ambivalent, 08 November 2022 - 02:54 PM.

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#1069 ambivalent

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Posted 09 December 2022 - 12:45 PM

Over the last few days I have what seemed to be a bacteria linfection, judged by the mucous-colour. Upped vitamin C and took quite excessive vitamin D and too tookseveral grams  liposomal fisetin + quercitin a couple of days in and then yesterday.  I have been surprised at how quickly it has arrested, they tend to last for much longer. it could have been the mega dose vitamin D, which I have used in the past on tooth abscesses to great effect, but I have naturally wondered about fisetin. While there is limited data, a quikc seatch does seem to reveal real promise as an antibiotic - though not much research since its role as an antibiotic was first posited:

 

From 1966:

 

THE antibacterial effect of numerous bioflavonoids is not yet known, and on the basis of chemical structure it seemed worth while to investigate the possible antibacterial effect of fisetin, dihydrofisetin and fisetinidin chloride. Fisetin and dihydrofisetin are commercial products, but we have synthesized fisetinidin chloride. Fisetin is found in Butea frondosaGleditschia triacanthosQuebracho Colorado and the genus Rhus1,

A patent application updated this year from China for fighting listeria:

 

"The invention relates to application of fisetin in preparation of a drug for resisting listeria infection. It is proved that the drug has the effect of resisting listeria infection by a sheep red blood cell hemolysis test, a protection test of mouse macrophage-like cell J774 and mouse peritoneal macrophages damage, and a mouse listeria infection model. Compared with treatment by antibiotic, treatment by fisetin has the characteristics of being free of drug tolerance and high in recovery rate. Therefore, fisetin can be for developing a new drug, and has significance on confirming of drug targets." (related listeria study)

 

 

"In this paper, we isolated and identified the first multi-resistant pathogenic Serratia marcescens strain from diseased soft-shelled turtles (Pelodiscus sinensis) in China. We then performed a checkerboard assay; the results showed that out of 10 tested natural products fisetin had synergistic effects against S. marcescens when combined with norfloxacin. The time-kill curve assay further confirmed the results of the checkerboard assay. We found that this novel synergistic effect could significantly reduce the dosage of norfloxacin against S. marcescens."
 
 
"Our results have demonstrated that fisetin can be a novel and effective compound to prevent and treat SC19 infection. However, there is much room for further study. In vitro, the inhibitory rate of fisetin on the hemolytic activity of suilysin can reach >85%. However, in vivo, the survival rate of infected mice treated with fisetin approximates 40%. Therefore, further research could improve the therapeutic efficacy of fisetin in clinical application by optimizing the structure and dosage of fisetin and changing the treatment route or using fisetin in combination with other antibiotics.

 


Edited by ambivalent, 09 December 2022 - 01:03 PM.

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#1070 ambivalent

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Posted 18 January 2023 - 03:53 PM

A good article, emphasizing the spectrum of effects that might reasonably be expected through fisetin supplementation:

 

https://supplements....tin-1-favorite/

 

Also, I would offer some endorsement to the reddit poster's claim of turning white hair to grey. I noticed it in the summer, strikingly in the hairdressers, but the sun can sometimes have such an effect, though I thought it was still exceptionally unusual. During an out of summer season clip last month, I was once again struck, more so, by the colour and subsequently convinced  it had changed. It was noted too by people who hadn't seen me for months. This is very likely fisetin, but which brand? I started taking the F+Q supplement a few weeks before I paid attention during the summer, but it could have been this way before I began F+Q and I had been out in the sun. 

 

So it was either grams of this mixed with olive and possibly lecithin and or the liposomal form. Hopefully, it represents a pleasant indicator of wider senescent cell clearance induced rejuvenation. 


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#1071 manofsan

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Posted 23 January 2023 - 11:10 AM

But what are the concerns about Senolytics like Fisetin again?  Is it that their frequent use can accelerate telomere shortening?

 

I forget what the argument was, but I know that some argument had been made against Senolytics.


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#1072 osris

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Posted 24 January 2023 - 06:08 PM

I see in the comments section that people wondering about the administration of the Fisetin in the ITP program and whether or not they did mass spec on the the blood samples.

 

Yes, the comments also criticised Brad for not mentioning that the ITP had not used fisetin mixed with an oil substance to make it bioavailable. 



#1073 Empiricus

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Posted 25 January 2023 - 12:22 PM

But what are the concerns about Senolytics like Fisetin again?  Is it that their frequent use can accelerate telomere shortening?

 

I forget what the argument was, but I know that some argument had been made against Senolytics.

 

The main concern with fisetin is that it may delay healing of injuries.  That's based on anecdotes of users.


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#1074 Meggo

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Posted 26 January 2023 - 06:11 AM

Are there any bulk fisetin vendors inside the EU?



#1075 ambivalent

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Posted 26 January 2023 - 05:31 PM

But what are the concerns about Senolytics like Fisetin again?  Is it that their frequent use can accelerate telomere shortening?

 

I forget what the argument was, but I know that some argument had been made against Senolytics.

 

 

This is the link on telomeres:

 

https://www.ncbi.nlm...les/PMC3844163/

 

In vitro and with DMSO, which could confound things. Fisetin has been shown to extend the lifespan of mice with Huntingtons, though the disease is associated is characterised with shorter telomomeres - but that's with mice, and they have longer telomeres.

 

There have been a few accounts of wound healing including my own, but they are not frequently reported, but are consistent with the senescent cells signalling wound healing - but it certainly seems there was quick adaptation on my behalf. Here we have:

 

"Transiently induced senescence is required for development, regeneration and acute wound repair, while chronic senescence is widely implicated in tissue pathology. We recently demonstrated that sustained senescence contributes to impaired diabetic healing via the CXCR2 receptor, which when blocked promotes repair. "

 

My experience is certainly that there is not a permanent impact of the inhibition of "induced sensecence" - it certainly seemed as though there was adaptation. 

 

More senolytics and cancer

 

https://www.fightagi...arch-community/

 

I seem to remember, though couldn't immediately find cases of cancer patients bleeding to death using one senolytic many eyars ago iirc.  

 

There have been positive papers on fisetin and cancer and I will put some up at some point, though there has been concern that the toxicity of senescent cells is such that it can suppress tumour growth.

 

"Senescence can suppress tumorigenesis not only by limiting the malignant transformation of pre-neoplastic cells but also by halting the proliferation of tumor cells.  "

 

Fisetin, though is more than just senescent cell clearance. I will search for some fisetin/cancer papers at some point.  

 

Note: re the hair change colour mentioned in a previous post, this wasnt't from white to grey as might have been inferred but a lightening or partial restoration of my natrual colour. 

 


Edited by ambivalent, 26 January 2023 - 05:48 PM.

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#1076 ambivalent

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Posted 26 January 2023 - 09:38 PM

O/T Exosomes Derived from Fisetin-Treated Keratinocytes Mediate Hair Growth Promotion (in mice)

 

Fisetin mixed in ethanol, topically applied.

 

https://www.ncbi.nlm...les/PMC8234638/


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#1077 ambivalent

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Posted 26 January 2023 - 09:41 PM

O/T:  Fisetin and atherosclerosis:

 

Fisetin Prevents Oxidized Low-density Lipoprotein-Induced Macrophage Foam Cell Formation

 

https://pubmed.ncbi....h.gov/34173812/

 

"Foam cell formation is an important event in atherosclerosis."

 

"In conclusion, fisetin could inhibit foam cell formation by blocking oxLDL-induced ROS formation and subsequent NLRP3 activation, thereby inhibiting SREBP-1 and its downstream genes including FAS and HMGCR."


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#1078 osris

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Posted 31 January 2023 - 12:02 AM

I read somewhere on this forum, I can't remember where, that if you do the Mayo Protocol you shouldn't do it monthly... or rather you should take a month off between doing it. Is that true, and if so why?


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#1079 ambivalent

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Posted 14 July 2023 - 12:57 PM

I see in the comments section that people wondering about the administration of the Fisetin in the ITP program and whether or not they did mass spec on the the blood samples.

 

 

This guy puts out an attempt at a rebuttal to the study - believes the dosing level was too small:

 

https://youtu.be/IDOi0ODewjE?t=1985


Edited by ambivalent, 14 July 2023 - 12:58 PM.

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#1080 Woody42

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Posted 18 September 2023 - 09:16 PM

I saw one little vidio about taking 1 oz of freeze dried strawberrys ( about the equivelent of 1 lb of fresh ) to

fight esophagel cancer. So I wonder if the 65 mg of fin\setin you would get from this was fighting the cancer

of if it was orher bioactive compounds in strawberrys?

 

 

https://nutritionfac...phageal-cancer/


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