1079 replies to this topic

[OP2040]

what is the consensus on the highest quality brand FISETIN.        message me if it is more appropriate

 

I can't imagine quality being an issue, since it's a simple food derivative.  I bought from two different sources to get my two bottles.  One thing I would look for is that you want ONLY Fisetin.  Supplement makers love adding in extra stuff, I suppose to make it seem value-added.  But at the doses we want to take, we definitely don't want anything other than Fisetin in our purchase.

[OP2040]

Another good study, not sure if it's already been posted.  There are many studies on Fisetin

 

https://www.scienced...024320517305817

 

 

Our data demonstrated that fisetin significantly decreased the level of pro-oxidants and increased the level of antioxidants. Furthermore, fisetin also ameliorated mitochondrial membrane depolarization, apoptotic cell death and impairments in the activities of synaptosomal membrane-bound ion transporters in aging rat brain. RT-PCR data revealed that fisetin up-regulated the expression of autophagy genes (Atg-3 and Beclin-1), sirtuin-1 and neuronal markers (NSE and Ngb), and down-regulated the expression of inflammatory (IL-1β and TNF-α) and Sirt-2 genes respectively in aging brain.

Significance

The present study suggests that fisetin supplementation may provide neuroprotection against aging-induced oxidative stress, apoptotic cell death, neuro-inflammation, and neurodegeneration in rat brain.

 

 

It makes me question whether it should be taken intermittently or not.  There are seemingly a lot of other benefits aside from being a senolytic.  It would be nice to know if the senolytic activity is driving all the other benefits or if they're separate.

[Supierce]

What does it mean? Orally for 2 consecutive days for 2 consecutive months?

 

2 consecutive days per week for 2 months?
 

Two consecutive days the first month, then two consecutive days a month later.

[able]

Another good study, not sure if it's already been posted.  There are many studies on Fisetin

 

https://www.scienced...024320517305817

 

 

 

It makes me question whether it should be taken intermittently or not.  There are seemingly a lot of other benefits aside from being a senolytic.  It would be nice to know if the senolytic activity is driving all the other benefits or if they're separate.

 

 

It would be great to know that the benefits are mostly due to the senolytic activity. 

 

But if there are additional benefit from regular usage, you can still take mega dose intermittently, a few days off, then smaller dosages daily until ready for another mega dose some months later.

[OP2040]

able,

That is true.  However, the way I interpret the mice study and in light ow what we know about senolytics, the second dose wouldn't need to be for another year at least, and possibly for 5-10 years.  It sounds crazy, but if you clear senescent cells, you clear them right?  There is no benefit, and a possible detriment to continuing at that point.  I don't think the rate of accumulation is such that if I clear 40 years worth of senescent cells (theoretically), I will need to do the very same thing next month and not even next year.

[Turnbuckle]

 It sounds crazy, but if you clear senescent cells, you clear them right?  There is no benefit, and a possible detriment to continuing at that point.  I don't think the rate of accumulation is such that if I clear 40 years worth of senescent cells (theoretically), I will need to do the very same thing next month and not even next year.

 

 

Your body clears senescent cells all the time, thus you are unlikely to accumulate decades of senescent cells. But the rate of new senescent cells increases steadily with age even as the mechanisms for removing them start to malfunction. The burden of senescent cells begins to creep up and it doesn't take many to cause a problem. They are a source of inflammation and exhibit a distinctive secretory phenotype that damages nearby cells. They thus have an outsized effect for their numbers.

 

Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.

https://www.ncbi.nlm...les/PMC4166495/

 

 

With aged individuals, large numbers of cells are reaching the Hayflick limit and becoming senescent, thus senescence accelerates at that point. Cells are also becoming epigenetically old as well, thus it makes sense to eliminate them and replace them with zero age stem cells. This is something you wouldn't do every day, of course, but maybe once every few weeks for people over sixty.

Edited by Turnbuckle, 10 October 2018 - 03:48 PM.

[OP2040]

All I know is that most, if not all of the studies have shown intermittent clearance.  If you are taking large doses every couple weeks that is way too much and it's no longer truly intermittent. especially for a human time scale.  We don't have any evidence for what would happen with such a protocol.  At best nothing since the intermittent dose is already really striking, and at worst tissue dysfunction based on losing the valuable signals for regeneration and/or cancer prevention that senescent cells are known to cause.

 

Agreed that long term replicative senescence and stem cell loss will require some sort of replacement strategy.

[Krell]

age73, 183lb, 6ft, fit, no prescription drugs.

 

Started yesterday at 3PM on first of 3 daily 1000mg/day doses of fisetin in 2tbsp (30ml) olive oil.

 

The fisetin olive oil mixture had no taste other than the olive oil.

 

Over the first 24 hours I did not notice any effects other than perhaps vivid dreams (or was that just a dream?).

This morning I played tennis and worked out with no changes noted. My tennis serve was not improved.

 

Took my blood pressure this morning and last evening and they were both normal/typical.  Also took automated heart

rate measurements every few minutes day and night with my Garmin 235 watch, and they were normal/typical also.

 

I took the second fisetin 1000mg dose at 3:15PM today.

 

I have suspended my usual daily supplements for this 3 day trial (5000iu D3 and 400mg proanthocyanidins grape seed extract)

I did continue my daily dark chocolate and daily glass or two of high proanthocyanidin wine (Madiran).

 

I wonder of my high proanthocyanidin diet over many years has already given me the benefits expected from fisetin?

 

My yearly physical with blood test is at the end of October.  Any extra tests I should order?

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[sthira]

Scant fasting studies in humans (>5 days) offer hints that the body may tear down damaged cells to recycle for energy, and the body may expel other useless, damaged cells.

So I wonder about the effects of a self-experiment that includes fasting, and, narrowing in, on fasting days, say, 5, 6, and 7 (wild guessing) consume high doses fisetin dissolved into olive oil, lecithin, ethanol.

Maybe eat a pound or two of strawberries in conjunction, breaking the fast -- maybe there's something in that complicated matrix of a strawberry (that is then turbo-charged by fisetin pills) that might offer more senescent cell killing potential? Hope you kill the right cells, though....

Personally, I think it's nuts to try this on your precious complicated biology based on some promising rodent studies; but if you're gonna do it anyway, how to maximize it?

But to me the big hanging black cloud over any self-experiment of any pill or potion is how would you even know if what you took did what you wanted it to do?

Think you'll "feel" it? If you killed and expelled senescent cells via any protocol how would you know? Saying "My age spots disappeared" isn't totally useless, I guess, but I also think you'll have to prove those sun spots disappeared with before and after pictures, and then we'll all have to believe it.

"Reason" over on FightAging offers helpful guides to self experimenters. Have you read those guides?

[able]

Scant fasting studies in humans (>5 days) offer hints that the body may tear down damaged cells to recycle for energy, and the body may expel other useless, damaged cells.

So I wonder about the effects of a self-experiment that includes fasting, and, narrowing in, on fasting days, say, 5, 6, and 7 (wild guessing) consume high doses fisetin dissolved into olive oil, lecithin, ethanol.

Maybe eat a pound or two of strawberries in conjunction, breaking the fast -- maybe there's something in that complicated matrix of a strawberry (that is then turbo-charged by fisetin pills) that might offer more senescent cell killing potential? Hope you kill the right cells, though....

Personally, I think it's nuts to try this on your precious complicated biology based on some promising rodent studies; but if you're gonna do it anyway, how to maximize it?

But to me the big hanging black cloud over any self-experiment of any pill or potion is how would you even know if what you took did what you wanted it to do?

Think you'll "feel" it? If you killed and expelled senescent cells via any protocol how would you know? Saying "My age spots disappeared" isn't totally useless, I guess, but I also think you'll have to prove those sun spots disappeared with before and after pictures, and then we'll all have to believe it.

"Reason" over on FightAging offers helpful guides to self experimenters. Have you read those guides?

 

I am fasting now and will take 2 dosages at at the end of my fast Thursday and friday (in olive oil).

 

I agree that being able to "feel" a benefit is quite difficult to judge.  Reduced joint pain would be slightly less subjective, but that varies for me quite a bit from day to day anyways, so it might be encouraging to notice, but certainly not proof.

 

"My age spots disappeared" would be meaningful, but seems overly optimistic from taking Fisetin orally.  

 

I will also mix some in DMSO and apply to arm and leg on the left side, so if there is any change from the topical application it might be more noticeable.

[extendcel]

It is possible that the doses are just too small. The bioavailability is a lot lower in humans compared to mice, so a direct HED conversion will result in a lower actual dosage. In addition, the study states:

"For oral administration of fisetin, mice were dosed with 100 mg/kg of fisetin in 60% Phosal 50 PG:30% PEG400:10% ethanol or vehicle only by gavage."

The oral vehicle used 60% conc phospholipid-propylene glycol mix and 30% conc. PEG400 which is a strong solvent, followed by 10% ethanol which is another solvent. This vehicle would significantly increase oral bioavailability.

So not only are people intaking a dose resulting in lower bioavailable absorption, but also using a different vehicle (weaker) than the study.

Edited by extendcel, 10 October 2018 - 09:02 PM.

[Heisok]

"But if there are additional benefit from regular usage, you can still take mega dose intermittently, a few days off, then smaller dosages daily until ready for another mega dose some months later." I agree that this a a valid possibility.

 

I see this Fisetin experiment as similar to those who have done courses of Dasatanib with/without Quercetin.

 

Stephan mentioned "Woke up in morning: slight painfull feeling in lungs, some cough"

 

My immediate reaction was to think back to the Logic warning as the Dasatanib group was being finalized. Essentially it was that those with possible lung issues should be very careful. It was specific to Dasatanib, but maybe the same warning applies here.

 

 

[ryukenden]

Two consecutive days the first month, then two consecutive days a month later.

Ok thanks

[stefan_001]

"But if there are additional benefit from regular usage, you can still take mega dose intermittently, a few days off, then smaller dosages daily until ready for another mega dose some months later." I agree that this a a valid possibility.

 

I see this Fisetin experiment as similar to those who have done courses of Dasatanib with/without Quercetin.

 

Stephan mentioned "Woke up in morning: slight painfull feeling in lungs, some cough"

 

My immediate reaction was to think back to the Logic warning as the Dasatanib group was being finalized. Essentially it was that those with possible lung issues should be very careful. It was specific to Dasatanib, but maybe the same warning applies here.

 

Thats indeed good to remember:

Tyrosine kinase inhibitors have revolutionized the treatment of chronic myeloid leukemia and are increasingly used for other indications. Fluid retention, however, including pleural effusions, are a significant side effect of imatinib, the first-line treatment for chronic myeloid leukemia. We investigated pleural and pulmonary complications in patients treated with dasatinib, a novel multitargeted tyrosine kinase inhibitor, as part of clinical trial protocols. Of 40 patients who received dasatinib (70 mg twice daily) for imatinib resistance or intolerance, 9 (22.5%) developed dyspnea, cough, and chest pain. Of these nine patients, six had pleural effusions (all were exudates) and seven had lung parenchyma changes with either ground-glass or alveolar opacities and septal thickening (four patients had both pleural effusions and lung parenchyma changes). Lymphocytic accumulations were detected in pleural and bronchoalveolar lavage fluids in all patients except for one who presented with neutrophilic alveolitis. Pleural biopsies revealed lymphocytic infiltration in one patient and myeloid infiltration in another. After dasatinib interruption, lung manifestations resolved in all cases and did not recur in three of four patients when dasatinib was reintroduced at a lower dose (40 mg twice daily). Thus, lung physicians should be aware that lung manifestations, presumably related to an immune-mediated mechanism rather than fluid retention, may occur with dasatinib treatment.
 

[OP2040]

I'll lay it out like this.

a. Individual is healthy with no age-related disease or dysfunction, or even very limited disease or dysfunction

b. Individual takes small, large, no dose of Fisetin

c. Individual remains healthy with no age-related disease or dysfunction.

 

What do we conclude from this?  Hint: "Fisetin doesn't do anything" is the wrong conclusion

 

I understand this isn't the majority of posts,  Most posts are more ambiguous.  A person  has some aches and pains, grey hair, age spots, whatever. But there are almost no posts of individuals who probably should be the ones taking this.  That is, people with age-related disease or dysfunction.  Some of these less important things probably are good for spot checking whether something works.  But in reality, it would be just as revolutionary if age spots and grey hair stopped increasing for 1-10 years as it would for age reversal.  I don't think we are at the level of age reversal with senolytics, but stretching out health-span would still be a really huge thing.

 

Then there is the issue of people still saying this is high risk.  I do think it is too much risk for someone who is younger and healthy.  I don't understand why a relatively young, healthy person would do this.  But the situation totally changes for anyone over 40 or anyone with age-related disease.  In these situations, you are actually already dying.  No amount of exercise or eating kale is going to save you.  At this stage you have to start taking actions or the dying process will continue. Perhaps it will continue in a stable way for 30-40 years, but no question it will continue.  Some people are ok with that, but more often I think people are just in denial about it.  That's why you get people saying that taking a strawberry extract in high doses is terribly high risk and even stupid. 

 

Lets say you are stranded on an island, and you will run out of nutrition in about 1 year.  In this situation is building a raft asap, before you become weak from hunger, then attempting to navigate off the island a hugely risky, stupid decision, or a rational one?  To me, that is the correct analogy.  And the person who is in complete denial and scared of any and all actions, who thinks the status quo is just fine, is completely irrational.

[OP2040]

I remember back when I was investigating cyclodextrin, it was shown to cause hearing problems.  Cyclo was effectively clearing arterial plaques, but something within those plaques was also necessary for the proper structural maintenance of inner ear hairs.  No doubt, we could find some similar paradox with the clearance of senescent cells.  The game right now is to clear most of them, because they probably are an essential part of biological process when kept at the same levels as a young person.  Having said that, there's been a lot of senescent cell clearance in animals in the last few years, and I haven't heard of anything like that yet, particularly with Fisetin.

Edited by OP2040, 11 October 2018 - 02:02 PM.

[able]

Took my first dose  yesterday.  3 grams, in olive oil.  

 

Nothing exceptional to report.

 

Slept great last night and feel great today.  

 

Hoping that means no damage done, and possibly some benefit.

 

Plan to increase to 4 grams today.

[OP2040]

3-4 grams is a lot.  This should allay all the fears over mega-dosing, assuming you survive

[Alpharius]

I will take Dasatinib (TeamTLR) with Fisetin in the next days. Probably 75-100 mg Dasatinib and 2000 mg Fisetin. Only one day, should be enough.

[John250]

"But if there are additional benefit from regular usage, you can still take mega dose intermittently, a few days off, then smaller dosages daily until ready for another mega dose some months later." I agree that this a a valid possibility.

I see this Fisetin experiment as similar to those who have done courses of Dasatanib with/without Quercetin.

Stephan mentioned "Woke up in morning: slight painfull feeling in lungs, some cough"

My immediate reaction was to think back to the Logic warning as the Dasatanib group was being finalized. Essentially it was that those with possible lung issues should be very careful. It was specific to Dasatanib, but maybe the same warning applies here.

What about if you just take 100mg 2x/day year round?

[Oakman]

What about if you just take 100mg 2x/day year round?

 

Or even 100 mg once a day, as the label says. Can that be so wrong?

[John250]

Or even 100 mg once a day, as the label says. Can that be so wrong?

Too hard to go off label claims. Take vitamin C for example. Claims are far too low. But then again some supplements are accurate.

[Oakman]

^ Agreed, label recommendations are suspect. But more to the point, as senescence is a natural process, increasing with age, the problem is improving / increasing the disposal of aging byproducts as we get older.  Perhaps gentle encouragement from a small dose of a senolytic like fiestin, over a continuous period, will be sufficient, and (mostly) keep up with the aging process. At least, it's an alternative to massive dosing on an intermittent basis.

[extendcel]

The main issue with small doses is metabolism by the liver. You may not receive any effects at all with low doses if it is quickly metabolized into inactive conjugates.

[Oakman]

The main issue with small doses is metabolism by the liver. You may not receive any effects at all with low doses if it is quickly metabolized into inactive conjugates.

 

Yes a problem and limitation. Weird there is no commercial nanoparticle or liposomal fisetin to help keep dosing low AND effective. They've been studied.

[extendcel]

Yes a problem and limitation. Weird there is no commercial nanoparticle or liposomal fisetin to help keep dosing low AND effective. They've been studied.

A commercial liposomal formula isn't viable due to the sheer volume you would need as a result of the poor solubility. This goes for non-liposomal nanoparticle formulas too. In addition is the use of surfactants and solvents in nanoparticle systems that would make it illegal to be sold as a dietary supplement.

I do plan on making my own liposomal fisetin though. There is one online source claiming fisetin has around 5mg/ml solubility in water, though I'm not sure how accurate this is.

Edited by extendcel, 12 October 2018 - 02:36 AM.

[OP2040]

I'm in the mega-dosing camp for this very reason.  As you can see with the delivery issues, it gets very complicated very fast.  Delivery issues need to be solved eventually.  I have a feeling if they were solved, we would already be much further along.

[Oakman]

A commercial liposomal formula isn't viable due to the sheer volume you would need as a result of the poor solubility. This goes for non-liposomal nanoparticle formulas too. In addition is the use of surfactants and solvents in nanoparticle systems that would make it illegal to be sold as a dietary supplement.

I do plan on making my own liposomal fisetin though. There is one online source claiming fisetin has around 5mg/ml solubility in water, though I'm not sure how accurate this is.

 

What I see is reviewing the literature is successful in vivo and in vitro formulations of fisetin with significant bioavailabilities over free fisetin, so the question, "Why are these not produced commercially?"

 

https://www.research...itumor_efficacy

 

"In vivo, liposomal fisetin allowed a 47-fold increase in relative bioavailability compared to free fisetin."

 

https://www.scienced...928493116306117

 

"when the fisetin nanoemulsion was administered intraperitoneally, a 24-fold increase in fisetin relative bioavailability was noted, compared to free fisetin. Additionally, the antitumour activity of the fisetin nanoemulsion in Lewis lung carcinoma bearing mice occurred at lower doses (36.6 mg/kg) compared to free fisetin (223 mg/kg)."

 

https://www.ncbi.nlm...pubmed/27524059

 

"Results showed NPs having a mean diameter of 140–200 nm, and a percent loading of FS ranging from 70 to 82%. In vitro release studies revealed that NPs are able to protect and preserve the release of FS in gastric simulated conditions, also controlling the release in the intestinal medium. Moreover, the DPPH and ABTS scavenging capacity of FS, as well as α-glucosidase inhibition activity, that resulted about 20-fold higher than commercial Acarbose, were retained during nanoencapsulation process. "

[QuestforLife]

I don't see what would be so hard about making liposomal fisetin.

But I intend to try it dissolves either in oil or wine first, after taking a likewise amount of quercetin first to keep the liver enzymes busy.

[johnross47]

Is there any information/study on successive dosing with fisetin? It was reported (someplace here) that it eliminates 20%-50% of senescent cells in various tissues. I have taken 600mgs per day for 5 days and hope that it will eliminate at least some of the SCs. If I then take a repeat dose of 600  x 5 in six months time will it remove the same proportion or is there something special about the SCs that it removes, making the remaining SCs difficult to get rid of? Do SCs go through stages with only some stages being susceptible to removal?