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Fisetin: Senolytic!

fisetin senolytic

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#61 micro2000

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Posted 05 October 2018 - 08:14 PM

If absorption is an issue wouldn’t be best to order it in rolled powder add some bacteriostatic water and inject it?


If its like any of the other polyphenolics, then it has shit solubility in most solvents. I've made resveratrol and pterostilbene into injectables with PEG400 and they leave a painful lump.

#62 Daniel Cooper

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Posted 05 October 2018 - 08:36 PM

The aqueous solubility is virtually nil.  It has some solubility in DMSO and ethanol.  Looks like it would be difficult to even make a liposomal preparation.  I suppose if it can be done with resveratrol  it can be done with fisetin.

 

 

 

 



#63 extendcel

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Posted 05 October 2018 - 09:59 PM

I believe the dose should be significantly higher than what is used in the study considering the metabolism by the liver in humans. I am attempting to get bulk fisten from chinese suppliers but the prices are high.
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#64 OP2040

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Posted 05 October 2018 - 10:46 PM

I’m going to start Monday, and go for the week. Can’t wait to hear all of your experiences.

#65 stefan_001

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Posted 06 October 2018 - 05:29 PM

I don't personally need a 100% guarantee on safety.  It sounds like it is more likely to have benefit rather than damage, so I am going to give it a try, using the 20 mg/kg dosage they use in the phase 2 human study.

 

My question is, what might help the effectiveness?

 

NAD+ helps distressed cells survive, which is not what we want for clearing senescent cells.  So I was thinking it might be good to try the Fisetin during the 2-3 days a week I am cycling off NMN - make sense?

 

Also wondering about fasting.  I practice periodic fasting, eating just one meal (dinner) a day, and periodically will skip dinner to make a 48 hour fast.  Does it make sense to try the fisetin during a fast?

 

Over the last years I have regularly done a month of Fisetin at 200mg a day. It subjective but my mind got a boost out f it. Recently I did a month at 300mg / day, typically it gives a the skin a smoother feeling. There have been earlier reports on potential senolytics properties so this report is not an anomaly.

 

The new dosing at 20mg a day is a first I read, it would mean about 1500mg for me. Tempting as the lower dose gave some plusses but not a sense of "permanent" improvement, more a tamping down of SASP that returns after stopping the Fisetin use.

 

The molecular weight is not that high, perhaps sublingual use is an option. In case TNMNK reads this thread, any views on whether the filler can be removed the same way as with NR?
 


Edited by stefan_001, 06 October 2018 - 05:31 PM.

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#66 stefan_001

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Posted 06 October 2018 - 05:56 PM

https://www.tandfonl...01.2018.1469025

 

Development of transethosomes formulation for dermal fisetin delivery: Box–Behnken design, optimization, in vitro skin penetration, vesicles–skin interaction and dermatokinetic studies


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#67 Alpharius

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Posted 06 October 2018 - 07:28 PM

Also the question arisis if Fisetin could replace Quercetin in the Dasatinib+Quercetin combination more effectively. It is highly probable that both kill senescent cells in a similar manner, with Fisetin beeing way more potent.


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#68 stefan_001

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Posted 06 October 2018 - 08:31 PM

started my safety study - took 1000mg, no NR, no other supplements


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#69 VP.

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Posted 07 October 2018 - 12:29 AM

Done with 1000 mg Quersetine day one and 1600 mg/day of Fisetin for two days. No other supplement except Rapamycin for this dosing period. Nothing to report so far. 


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#70 William Sterog

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Posted 07 October 2018 - 07:21 AM

I took 300mg, I'm slowly increasing the dose. Never felt a thing from 100mg, as I said earlier, but yesterday I experienced transitory feelings of sickess, some very mild stomach upsetting and, latter in the day, a noticeable reduction in inflammation followed by feelings of well-being. I have slept incredible well and I have had very vivid dreams. All of this could easily be placebo, but I repeat that I never experienced anything from 100mg a day and I was fairly hyped when I purchased the substance. 100mg a day was the recommended dose in the bottle.

Edited by William Sterog, 07 October 2018 - 07:22 AM.

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#71 stefan_001

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Posted 07 October 2018 - 08:01 AM

started my safety study - took 1000mg, no NR, no other supplements

 

Woke up in morning:

- slight painfull feeling in lungs, some cough

- skin on my hands is bit tighter but this is somewhat similar to using 300mg, its was not permanent then. My speculation is Fisetin at 300mg reduces SASP activity which is good too but means you need to use Fisetin constantly. Lets see what happens over the days with this higher dose.

- overall tired

 

At risk of spoiling the effect I did take NR in the morning. If Fisetin is selective it should have killed some cells during the 12 hour window. NR to help recover collateral damage. Will use another dose of 1000mg tonight and skip dinner.


Edited by stefan_001, 07 October 2018 - 08:03 AM.

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#72 OP2040

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Posted 07 October 2018 - 01:42 PM

Unfortunately my second bottle of FIsetin is held up in shipping so I'll be starting probably next week.

 

I was also thinking this could easily replace Rap + Q.  Unfortunately for me, it can probably even replace FOX04-dri, which I did buy and is now sitting in my freezer.  Oh well, I expect that this will happen a lot as time goes on and we get better and better knowledge and results.  Different interventions will come and go,  I'm still trying to wrap my head around the idea that it should only need to be taken at high doses very, very intermittently. 

 

What we need now more than ever is a very simple in vivo diagnostic test for senescent cells, or I guess SASP would do.  I've been reading up on it and it seems there are plenty tests/assays like SA B-Gal, or P16ink4a.  But they are done on cell cultures, and no idea how one would conduct such a test even if you wanted to take a before/after skin sample.  Any ideas on this front would be greatly appreciated. 

 

I never thought much about this with FOX04-dri because there was no way I would be doing before/after tests with a ~1000 product.  But this is now within reach with FIsetin.  We just need a test and it could easily be bought over and over to dial in the right doses, timing and effectiveness.


Edited by OP2040, 07 October 2018 - 01:44 PM.


#73 VP.

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Posted 07 October 2018 - 03:45 PM

Unfortunately my second bottle of FIsetin is held up in shipping so I'll be starting probably next week.

 

I was also thinking this could easily replace Rap + Q.  Unfortunately for me, it can probably even replace FOX04-dri, which I did buy and is now sitting in my freezer.  Oh well, I expect that this will happen a lot as time goes on and we get better and better knowledge and results.  Different interventions will come and go,  I'm still trying to wrap my head around the idea that it should only need to be taken at high doses very, very intermittently. 

 

What we need now more than ever is a very simple in vivo diagnostic test for senescent cells, or I guess SASP would do.  I've been reading up on it and it seems there are plenty tests/assays like SA B-Gal, or P16ink4a.  But they are done on cell cultures, and no idea how one would conduct such a test even if you wanted to take a before/after skin sample.  Any ideas on this front would be greatly appreciated. 

 

I never thought much about this with FOX04-dri because there was no way I would be doing before/after tests with a ~1000 product.  But this is now within reach with FIsetin.  We just need a test and it could easily be bought over and over to dial in the right doses, timing and effectiveness.

 

It's been 24 hours since I took my last 1600 mg dose of Fisetin. Besides some poor sleep last night I feel nothing. I will continue to take Rapamycin and Metformin because they have a fundamentally different  anti aging effect as far as I can tell. I'm 57 with the usual aches and pains of just getting older (onset frailty). I think we should all not tell what brand Fisetin we are using until a few weeks have passed so we can determine later if certain brands are better then others and reduce any placebo or nocebo effects. I had a Horvath epignetic clock test done a month ago and I am still waiting for my results. The strange thing is senolytics does not appear to change your epigentic clock.

 

 

A confounding aspect of biological aging is the nature and role of senescent cells. It is unclear whether the three major types of cellular senescence, namely replicative senescence, oncogene-induced senescence and DNA damage-induced senescence are descriptions of the same phenomenon instigated by different sources, or if each of these is distinct, and how they are associated with epigenetic aging. Induction of replicative senescence (RS) and oncogene-induced senescence (OIS) were found to be accompanied by epigenetic aging of primary cells but senescence induced by DNA damage was not, even though RS and OIS activate the cellular DNA damage response pathway.[42] These results highlight the independence of cellular senescence from epigenetic aging. Consistent with this, telomerase-immortalised cells continued to age (according to the epigenetic clock) without having been treated with any senescence inducers or DNA-damaging agents, re-affirming the independence of the process of epigenetic ageing from telomeres, cellular senescence, and the DNA damage response pathway. Although the uncoupling of senescence from cellular aging appears at first sight to be inconsistent with the fact that senescent cells contribute to the physical manifestation of organism ageing, as demonstrated by Baker et al., where removal of senescent cells slowed down aging.[43] However, the epigenetic clock analysis of senescence suggests that cellular senescence is a state that cells are forced into as a result of external pressures such as DNA damage, ectopic oncogene expression and exhaustive proliferation of cells to replenish those eliminated by external/environmental factors.[42] These senescent cells, in sufficient numbers, will probably cause the deterioration of tissues, which is interpreted as organism ageing. However, at the cellular level, aging, as measured by the epigenetic clock, is distinct from senescence. It is an intrinsic mechanism that exists from the birth of the cell and continues. This implies that if cells are not shunted into senescence by the external pressures described above, they would still continue to age. This is consistent with the fact that mice with naturally long telomeres still age and eventually die even though their telomere lengths are far longer than the critical limit, and they age prematurely when their telomeres are forcibly shortened, due to replicative senescence. Therefore, cellular senescence is a route by which cells exit prematurely from the natural course of cellular aging.[42]

https://en.wikipedia...pigenetic_aging



#74 OP2040

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Posted 07 October 2018 - 05:43 PM

I think you are correct on a few levels VP.  Senescent cells probably don't target aging per se.  That's why the intervention doesn't do anything to maximum lifespan.  Much like ROS, senescent cells serve both good and bad purposes in the body, and in a youthful body they are an indispensable part of that youthfulness.. 

 

I would say that for 57, all you have is a some aches and pains, than ya senolytics probably won't do too much for you other than keep your remaining years consistently tolerable. Things like telomeres, dna damage, and above all epigentic reprogramming, all of which are interrelated in some ways, will end up being the true game changers.  The Hallmarks basically say as much, by placing senescent cells and mitochondrial dysfunction squarely where they belong, in a separate category that exacerbates the already existing condition of aging.  My recommendation hly inclas always been that the major interventions we have now are very exciting for people with age-related diseases and for healthspan, which excludes most of the people on this forum who are already healthy enough to avoid a serious reduction in healthspan.

 

I would like to believe that removing bad things offers tissues an opportunity to rejuvenate to some extent, but I'm not sure that will happen in an environment where the epigentic clock already has plenty of ticks and telomeres have already shortened somewhat.  Limiting or even eliminating damage is only half the problem.  Initiating rejuvenation is a whole other matter.  That's because damage does not cause aging, and that theory of aging has been totally discredited.  Getting the junk out merely buys us healthy time until we can get our reprogramming game working.


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#75 VP.

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Posted 07 October 2018 - 06:45 PM

I've been taking Rapamycin and Metformin for 20 months and both have senolytic properties. Is that why I'm not seeing any differences after taking Fisetin? Even a mild senolytic taken weekly will slowly clear out senescent cells or the inflammatory byproducts of senescent cells. . 

https://www.ncbi.nlm...pubmed/28425952

https://www.nature.c...cles/ncb3195#f6


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#76 Oakman

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Posted 07 October 2018 - 07:10 PM

I would say that for 57, all you have is a some aches and pains, than ya senolytics probably won't do too much for you other than keep your remaining years consistently tolerable. 

 

Ah... humor from the mouths of babes...how old are you anyway?


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#77 William Sterog

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Posted 07 October 2018 - 07:26 PM

500mg of Fisetin today. Heavy antiandrogenic side effects. My balls feel little and soft and I feel too emotional and unstable, I rarely, if not ever, feel this way, except in the presence of other antiandrogens, like Reishi. Paradoxically, I have beaten multiple marks in my brain games today.

 

Also, for the first time in two or three years, I got a pimple. 


Edited by William Sterog, 07 October 2018 - 07:27 PM.

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#78 OP2040

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Posted 07 October 2018 - 08:03 PM

Ah... humor from the mouths of babes...how old are you anyway?

 

I think I come off as preachy or overly-ideological in these discussions.  I am aware of that, and I'm sure my posts get some eye rolls because it.  I come by that naturally, unfortunately.  To answer your question, I am 45.  But to address the topic, I see nothing controversial in what I said.  1/3 of people have high blood pressure which means write a bit more more than 1/3 of people over my age.  Almost all people past their 40s have myopia.  High cholesterol I'm sure could be added to the list though I'm not sure what the stats are on that one.  And those are just a few of the very crude age-related biomarkers we humans tend to concentrate on.  I would emphatically say that if you are 57 and have no measurable age related illness or dysfunction, you are exceptional. 

 

There can only be three reasons that I can think of why people on this forum rarely talk about their age-related dysfunction.  And I mean measurable things, not "aches and pains".  First, they are too young to have such.  Second, they are too healthy and exceptional compared to the general population to have such.  Finally, they are too shy/scared/in-denial to state such publicly.  No matter which of these it is, it is proving to be a real problem with how we judge the various interventions we take here.  Of course if you are healthy with only vague complaints, then it means absolutely nothing to say "this didn't make me feeeeeeel better".  Call me arrogant for saying this, but it's a real problem and I'm not excluding myself.  I am in the latter category.  I don't like the idea of discussing my health issues on a public forum.

 

There are other methodological issues as well.  Humans live for an extremely long time already, with a very long old age.  Who is to say that many of the people on this forum are not already benefiting from some of the interventions they are doing?  If you are doing an intervention at a young age, or when you don't have a measurable illness, there is no way to scientifically determine if it has any effect.  For that matter, it could eve extend your maximum lifespan, but you won't know it for 30-40 years.  I would like things here to be more scientific is all I'm saying, but I also realize that it's a forum full of health nuts, so it can never be such.   I look forward to an after measurement on that Horvaths clock, but only something like that will convince me one way or the other.  Even for myself, I experience plenty of aches and pains, but as we all know these things can be quite ambiguous.  Am I achy because of my posture, or because I have kidney disease.  Well, that's why we have tests!!! 

 

Even beyond this, I have seen a few brave souls who do report various Dr. visit tests.  I have seen when they report something very clearly positive, they are dismissed with whatever rationale that can be summoned.  I am thinking of the older gentleman who is taking NMN and reporting some very nice successes.  He's usually ignored or questioned.  This could be construed as a properly skeptical scientific attitude.  But I think its actually just a very ingrained negativity bias.  Because when the opposite happens and people report "this did nothing for me" with no tests, it is roundly believed and soon after the thread dies.  It is certainly not cold, rational scientific attitudes that are driving this behavior.


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#79 OP2040

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Posted 07 October 2018 - 08:08 PM

500mg of Fisetin today. Heavy antiandrogenic side effects. My balls feel little and soft and I feel too emotional and unstable, I rarely, if not ever, feel this way, except in the presence of other antiandrogens, like Reishi. Paradoxically, I have beaten multiple marks in my brain games today.

 

Also, for the first time in two or three years, I got a pimple. 

 

lol, see this is what I'm talking about.  I seriously don't mean to pick on you, because I do the exact same thing!!   We all want to feel good, and that's my main goal too.    But it's just an anecdote at the end of the day, tied into your daily routine, habits, expectations, diet, placebo, etc. etc.  Having said that, no shame in my game, I'd take a little gender confusion or puberty 2.0 over aging any day of the week lol.

 

Please, please don't get me wrong, I absolutely enjoy hearing this kind of feedback.  I'm just hoping we get some biomarkers from someone......anyone.   Cause I probably won't give them either :laugh:


Edited by OP2040, 07 October 2018 - 08:11 PM.


#80 William Sterog

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Posted 07 October 2018 - 09:27 PM

Yes, of course, I know that it is only an anecdote, but I'm very sensitive to antiandrogens, and Fisetin, both in my experience and later also by research, although only done in cancer, as far as I know, seems to be one.

https://www.ncbi.nlm...les/PMC2954499/

https://www.ncbi.nlm...les/PMC4631581/

I'm balding and my scalp feels much better today. I'm pretty sure that fisetin does something in terms of androgens.
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#81 Michael

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Posted 07 October 2018 - 10:46 PM

I've been taking Rapamycin and Metformin for 20 months and both have senolytic properties. Is that why I'm not seeing any differences after taking Fisetin? Even a mild senolytic taken weekly will slowly clear out senescent cells or the inflammatory byproducts of senescent cells. . 
https://www.ncbi.nlm...pubmed/28425952
https://www.nature.c...cles/ncb3195#f6

 
Neither rapamycin nor metformin are senolytic. The first study you cite show that metformin slows the rate at which cells become senescent ex vivo (which may or may not occur in vivo, and may or may not be beneficial if it does), not that it kills them. The second shows that rapamycin inhibits SASP in senescent cells — again, not that it ablates them.
 

I had a Horvath epignetic clock test done a month ago and I am still waiting for my results. The strange thing is senolytics does not appear to change your epigentic clock.
 

https://en.wikipedia...pigenetic_aging

 
There are several purported epigenetic aging clocks out there. The one you likely got (the first-generation Horvath clock, available commercially), and which is the subject of the Wikipedia article you cite, is tightly correlated with chronological age, not biological age, so you wouldn't expect it to follow any particular component of aging and isn't a good way to evaluate the effects of a potential anti-aging intervention.
 
The new Horvath epigenetic aging clock, DNAm PhenoAge (PMID 29676998) does closely track biological age, having been built up by machine learning from a series of (mostly) common blood test analytes; it would be a good test to use to evaluate putative anti-aging interventions; unfortunately, it's not commercially available. (Additionally, as the paper notes "In fact, but perhaps not surprisingly, the phenotypic age measure used to select CpGs [ie, the composite of underlying blood and other tests] is a better predictor of morbidity and mortality outcomes than DNAm PhenoAge." Unfortunately no one has turned this into a handy online calculator or app, though I wish someone would ...).
 

I think you are correct on a few levels VP.  Senescent cells probably don't target aging per se.  That's why the intervention doesn't do anything to maximum lifespan.

 
Senescent cells are clearly one of the cellular and molecular lesions driving biological aging. However, you can't expect targeting just one of the seven categories of aging damage to increase maximum lifespan, because of the "weakest link in the chain" effect: you have to hit all seven, including all specific lesions within each category.


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#82 extendcel

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Posted 07 October 2018 - 10:54 PM

The 2018 study on fisetin says mice were fed a 500mg/kg diet which translates to around 40mg/kg in humans.

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#83 VP.

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Posted 08 October 2018 - 03:46 AM

If the commercial epigenetic tests only test chronological change why does it not accurately measure centenarians age? I agree with your overall point but that's all we have now to measure biological age. 

 

The offspring of semi-supercentenarians (subjects who reached an age of 105–109 years) have a lower epigenetic age than age-matched controls (age difference=5.1 years in blood) and centenarians are younger (8.6 years) than expected based on their chronological age.[18]

https://en.wikipedia...ians_age_slowly


Edited by VP., 08 October 2018 - 03:49 AM.


#84 QuestforLife

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Posted 08 October 2018 - 08:11 AM

  
There are several purported epigenetic aging clocks out there. The one you likely got (the first-generation Horvath clock, available commercially), and which is the subject of the Wikipedia article you cite, is tightly correlated with chronological age, not biological age, so you wouldn't expect it to follow any particular component of aging and isn't a good way to evaluate the effects of a potential anti-aging intervention.
 

 

Finally, someone who is not in thrall to Horvath and actually understands that correlating methylation sites to chronological age does not necessarily mean you have captured the fundamental mechanism of aging.

 

Agree the PhenoAge clock would be preferable, when available. Perhaps we could get before and after blood tests using on the same tests PhenoAge is correlated to?


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#85 Andey

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Posted 08 October 2018 - 08:23 AM

Short version:

I took 200mg of Fisetin in lecithin + olive oil + 100mg of Dasatinib for two days.

The second day I 've experienced a flu-like reaction, beware. 

 

Long version:

I wrote it already in Turnbuckle`s stem cell protocol thread, but anyway 

I've stepped up on a hype train and done Fisetin bout myself.

 

I 've recalled somebody taking the whole Fisetin bottle at once here with a positive report.

Also, a phase 2 Mayo study used 20mg/kg for two days for their participants.

https://clinicaltria...=fisetin&rank=1

 

Based on that my expectation was that it's quite safe to take Fisetin in high dosages.

As it has poor bioavailability but lipophilicity above average I mixed and blended the content of 40+ capsules in a bowl with lecithin, olive oil, and water.

I took half of it (2000mg) with dasatinib 100mg for two days.

The first day was business as usual, second day around 2hours mark I felt the flu-like reaction, with heart rate jumped +20beats per minute, that lasted to the end of the day.

I've never experienced this on Q+D, though I need to mention that my dasatinib is from TLR and I don't really sure is it a real stuff.

My gut filling that second day was different because Fisetin stayed 24h in a phospholipid solution and formed some bioavailable conjugates.

BTW If I were to use it now(what I don't plan to do for at least a year) I would start with 500-700mg mixed with phospholipids, and I would stay it in a fridge for a day or two.

That flu-like thing was unpleasant and I hardly feel anything from supplements, I imagine it could be unsafe to take high dosages for really advanced age individuals.

 


Edited by Andey, 08 October 2018 - 08:33 AM.

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#86 Ducky-001

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Posted 08 October 2018 - 09:01 AM

To try this, yesterday evening I took 1,5g Fisetin and 1,5g Quercetin. The ammount of fistein is what was described on the bottle (100mg/pill). The pills theme self are heavier at more than 300mg/pill. I have enough Fisetin for 1-2 more rounds and plan to go at it again this evening. I slept well last night, and have not noticed anything special except maybe a heightened alertness. I took them as pills (15x fisetin pills + 3 x quercetin) pills last night. I may try to open the pills and dissolve in some olive oil next time.

 



#87 OP2040

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Posted 08 October 2018 - 12:25 PM

Finally, someone who is not in thrall to Horvath and actually understands that correlating methylation sites to chronological age does not necessarily mean you have captured the fundamental mechanism of aging.

 

Agree the PhenoAge clock would be preferable, when available. Perhaps we could get before and after blood tests using on the same tests PhenoAge is correlated to?

 

Count me in as someone who is very skeptical of Horvath's claims.  Even if it did approximate something, it's still far from clear what it is approximating, because it's certainly not "aging-in-itself".

 

As I understand it, PhenoAge does that, it includes a bunch of traditional markers, applies the usual math and statistical mumbo jumbo, and voila.... 

 

I don't think we will have a true age calculator until some time after we actually cure aging.  Having a calculator necessarily implies we already know all the details of what causes aging, and we don't.  The minute we do know that, we will probably be able to cure aging soon after.  So likely we will need to rely on rough guides right up until we have our cure. 

 

I'm much more interested in tests that will show us if a substance is actually doing what it says it is doing.  In this case, a broad, in vivo senescent cell or SASP test.  If we had such, it would solve a lot of problems. 

 

The David SInclair approach was fine.  He just used a bunch of normal lab tests you get from your Dr. and then plugged them into a site using some statistical method which is probably similar to PhenoAge.  To me, that was good enough for now.


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#88 OP2040

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Posted 08 October 2018 - 12:31 PM

I might do the olive oil thing too, makes sense.  I don't  think it's wise from a testing front to keep taking other supplements at the same time.  It confuses the situation.  But also, the whole point of this hype train is that Fisetin seems to be quite effective by itself, so I don't see the need to add in various stacks of other senolytics.  Maybe this is a legacy of the D+Q thing, because we have been told over and over that one senolytic is good for some tissues and not others, so a combination is needed.  Well, this is probably not true with Fisetin.  They tested quite a few tissues and it was effective in all of them as a senolytic.  I am quite happy to make things simpler when it can be done, and therefore don't plan to take any other senolytics until or unless something better and more proven comes along.



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#89 johnross47

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Posted 08 October 2018 - 01:21 PM

Started on fisetin today. I'm 71 with several issues, most importantly, barely controlled asthma with a lot of inflammation on the lungs and arthritic joints in my hips and thumbs. I took 300mgs at first and after experiencing no effects took another 300 an hour later. Then Iwent for a run up our local hill with no ill effects. The run went well. I'm planning to take 600 per day for 5 days, and then wait at least six months before redosing. It's going to be hard to know whether or not there are any beneficial effects unless there are visible changes, or the asthma and/or arthritis improves significantly. I've paused my NR for the duration.


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#90 StanG

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Posted 08 October 2018 - 04:50 PM

"In the present study, the results of ALT and AST assays suggested that the fisetin dosage of 223 mg/kg may aggravate liver burden due to poor bioavailability. Further studies regarding increasing the bioavailability and reducing dose are required"

 

That's a huge amount to take - who in their right mind takes that much. Also, Fisetin has not been overlooked and some of these posts surprise me. I've been taking 100mg daily for several years, ever since I found out all the potential benefits it had. The results of the study only make take this stronger.


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