1079 replies to this topic

[Moondancer]

[...]

 

 

Rapamycin (and probably berberine) seem tohave more direct beneficial effect of stem cells but lowering SASP does seem to perk them up. 

 

All that said, D is hard to get and its side effects make you feel washed out while you take it (my experience was 3 days at 60mg once a day with 1000 mg Q and 1500 mg F). Rapamycin is even worse with reports of mouth sores, eye sores, deep acne and mild sexual dysfunction in the R thread.

 

Now the good news. Theaflavin also targets the BCL-2 path way like D and Berberine targets mTOR1 like R, both without side effects. Fisetin is an effective senolytic agent in 20mg/kg (1500mg-ish) all by itself and synergizes with D and T. 

 

I've been slowly adjusting my stack and am planning my next run to be 3000 mg liposomal F, 1000mg Q, still looking for dosing guidance on T but probably in the 1000-2000mg range, 1000mg berberine with chocolate (adds emulsified oil and lecithin - and taste),10mg bioperine and 400mg bromalin to aid absorption. (60, M, 6'2", 180lbs, good general health, good diet and exercise) I recommend not doing other things while doing these and I do a run for 2-3 days and then take off a minimum of two weeks, though many (like the Mayo clinic trial) run every week - 2 on 5 off, but just fisetin. My research has shown that chronic administration eventually seems to start causing undesirable side effects which might be tolerable if one was treating a specific disease, but not for what I need as the acute dosing seems to lead to durable effects without side effects. 

 

Hope this was useful.

 

 

Thanks again, DJSwarm. As to the beneficial effects of Rapamycin on stem cells: do you suggest a combination of for example of Rapamycin (or potentially Berberine, as seems to have your preference), with SC-removal may be 'more optimal'. And how would you suggest combining the two? 

 

I just found a publication that may be interesting with this regard: "Finally, rapamycin and other compounds have been demonstrated to have significant senotherapeutic effects (i.e. selective ability to restore or eliminate senescent cells) [5,6]. Many senotherapeutic drugs have minimal side effects and are effective with transient dosing. For example, at our clinic we routinely study the senotherapeutic drug fisetin, a phytonutrient with potent senolytic ability, and are conducing multiple randomized trials for its use in the context of osteoarthritis, an age-related pathology. Not only has rapamycin has been demonstrated to reduce senescence in MDSCs by our group [5], but others have demonstrated that blocking mTOR reduces stem cell senescence and associated secretory phenotypes [3,7]. In orthobiologic applications, the use of senotherapies like rapamycin is very compelling to reduce the anti-regenerative senescent profile of autologous stem cell therapies like bone marrow concentrate in various orthopedic indications." https://www.ncbi.nlm...les/PMC7467370/

 

 

It makes me wonder if one may not first start to use Rapamycin for a while (intermittent dosing seems common with this regard, as recommended by Dr. Green), before adding in the senolytics in a hit-and-run-fashion?

 

As to using liposomal Fisetin. I thought of simply mixing fisetin and Theaflavin with lecithin in a high speed blender. I remember a thread at Longecity where a patent was discussed that claimed that even without using ultrasonication this would result in the formation of liposomes. (Albeit I still have a ultrasonic cleaner I once bought for this purpose, but never used).

 

I know studies have confirmed bioperine could increase absorption, but could I ask how you came to the conclusion that bromalin may aid absorption?

And in case I missed it, were there any studies posted that confirm the senolytic properties of apigenin?

 

Sorry for the many questions, but do you suggest adjusting the dose of Fisetin and Theaflavin based on weight? (I also ask since my weight is about half of your weight).

 

 

 

Edited by Moondancer, 18 January 2022 - 03:13 PM.

[DJSwarm]

 

 

So show me some studies to support your position.

 

And yes, after starving for a while, when you eat you feel great. Doesn't mean it is useful or necessary. Also this is a senolytic thread and you were discussing your stack for a senolytic run - unless stated otherwise the assumption is that it is for senolytic purposes and it seems disingenuous to imply otherwise after the fact when called on your side effects.

 

And yes, feeling bad is almost always a sign of something bad happening along with what ever good is supposed to happen and uncontrolled bleeding is no joke.

 

I can find paper after paper on the benefits of intermittent fasting, time restricted eating (which seems to be the actual key), and fasting mimicking diets.

 

Long fasts, I mainly see anecdotal evidence from true believers. There sure is a lot on the "detox" myth though.

 

There is some evidence that Fasting triggers stem cell regeneration of damaged, old immune system (Studying chemo patients):

 

In the first evidence of a natural intervention triggering stem cell-based regeneration of an organ or system, a study in the June 5 [2014] issue of the Cell Stem Cell shows that cycles of prolonged fasting not only protect against immune system damage — a major side effect of chemotherapy — but also induce immune system regeneration, shifting stem cells from a dormant state to a state of self-renewal.

 

The study has major implications for healthier aging, in which immune system decline contributes to increased susceptibility to disease as people age. By outlining how prolonged fasting cycles — periods of no food for two to four days at a time over the course of six months — kill older and damaged immune cells and generate new ones, the research also has implications for chemotherapy tolerance and for those with a wide range of immune system deficiencies, including autoimmunity disorders.

 

This tracks with fasting activating ISR and other conservation steps. Note: they call out that during the fast WC dropped - stop the fast if you get sick.

 

You however; seem to be shutting down some blood clotting factor / platelets; and, I see absolutely nothing to support what you are doing.

[Moondancer]

So show me some studies to support your position.

 

And yes, after starving for a while, when you eat you feel great. Doesn't mean it is useful or necessary. Also this is a senolytic thread and you were discussing your stack for a senolytic run - unless stated otherwise the assumption is that it is for senolytic purposes and it seems disingenuous to imply otherwise after the fact when called on your side effects.

 

And yes, feeling bad is almost always a sign of something bad happening along with what ever good is supposed to happen and uncontrolled bleeding is no joke.

 

I can find paper after paper on the benefits of intermittent fasting, time restricted eating (which seems to be the actual key), and fasting mimicking diets.

 

Long fasts, I mainly see anecdotal evidence from true believers. There sure is a lot on the "detox" myth though.

 

There is some evidence that Fasting triggers stem cell regeneration of damaged, old immune system (Studying chemo patients):

 

In the first evidence of a natural intervention triggering stem cell-based regeneration of an organ or system, a study in the June 5 [2014] issue of the Cell Stem Cell shows that cycles of prolonged fasting not only protect against immune system damage — a major side effect of chemotherapy — but also induce immune system regeneration, shifting stem cells from a dormant state to a state of self-renewal.

 

The study has major implications for healthier aging, in which immune system decline contributes to increased susceptibility to disease as people age. By outlining how prolonged fasting cycles — periods of no food for two to four days at a time over the course of six months — kill older and damaged immune cells and generate new ones, the research also has implications for chemotherapy tolerance and for those with a wide range of immune system deficiencies, including autoimmunity disorders.

 

This tracks with fasting activating ISR and other conservation steps. Note: they call out that during the fast WC dropped - stop the fast if you get sick.

 

You however; seem to be shutting down some blood clotting factor / platelets; and, I see absolutely nothing to support what you are doing.

 

 

Another off-topic comment, but Longo has mentioned in several interviews that it is very difficult to get approval for studies wherein subjects fasts for longer amounts of time. (And that it would also be difficult to find study subjects interested in participating). So that would also explain why we have few of such studies. By now Longo of course also has a vested interest in his Fasting Mimicking Diet, but fact is that most earlier studies that showed benefits of fasting, focused on water only fasting.

 

Luigi Fontana stated in an interview that (as a result of a lack of such studies) it is impossible to draw any conclusions, but that he suspected that longer water fasts would have more significant systemic benefits than shorter fasts of a few days, with potentially significant benefits of regenerative nature. He referred to studies wherein subjects undertook shorter fasts, anecdotal reports about longer water fasts, but also reports coming from TrueNorth Health Center where patients regularly undertake longer water fasts. He also explicitly stated that he had seen no prove yet that the Fasting Mimicking Diet could yield similar results. It should be said he also emphasised he would not recommend undertaking a longer water fast because of potential risks associated with it. (He also is a medical doctor, so I can imagine he is careful in his recommendations). But he stated he could imagine a future wherein people would undertake periodic supervised longer water fasts to decrease the risk of different age-related diseases.

It has been years since I read this interview. I will see if I can still find it to add as a reference.

Edit to add: I can't find the interview currently. But here a statement of Dr. Alan Goldman from the TrueNorth Health Center in a Podcast, with regard to the comments in this thread that there are few studies involving longer water fasts. And why this lack of studies is not indicative for a lack of potential benefits from longer water fasts. (Sorry for the horrible 'paste': I'm unable to remove formatting)

"The other thing that's made a big difference is we've published a number of papers in peer-reviewed medical literature. ER including on the safety of fasting and the effect of fasting on high blood pressure. We've recently finished a study with the Mayo Clinic looking at primary prevention of stroke that's in review right now two major journal. We're hoping that we'll get positive publication of that here in the next couple weeks. We've done a study with Luigi Fontana from Washington University looking at biomarker changes in the gut microbiome before and after fasting right. We have a couple other studies that we're enrolling in right now. So now we're getting some Nations with some of these major players like Valter Longo, which is going to allow us to get into journals that we might not otherwise have been able to access because of the power that these guys bring yeah his nose his talent ability and his pedigree

 

I would imagine it's very helpful.

Oh, he's unbelievable just fabulous work and he's wonderful guy. Yeah, we're so fortunate that we've got these kind of people out there trailblazing into the scientific and medical literature because as clinicians and particularly Alternative 

https://podclips.com/ct/TDIamL

 

Edited by Moondancer, 18 January 2022 - 07:51 PM.

[ambivalent]

So show me some studies to support your position.

 

And yes, after starving for a while, when you eat you feel great. Doesn't mean it is useful or necessary. Also this is a senolytic thread and you were discussing your stack for a senolytic run - unless stated otherwise the assumption is that it is for senolytic purposes and it seems disingenuous to imply otherwise after the fact when called on your side effects.

 

And yes, feeling bad is almost always a sign of something bad happening along with what ever good is supposed to happen and uncontrolled bleeding is no joke.

 

I can find paper after paper on the benefits of intermittent fasting, time restricted eating (which seems to be the actual key), and fasting mimicking diets.

 

Long fasts, I mainly see anecdotal evidence from true believers. There sure is a lot on the "detox" myth though.

 

There is some evidence that Fasting triggers stem cell regeneration of damaged, old immune system (Studying chemo patients):

 

In the first evidence of a natural intervention triggering stem cell-based regeneration of an organ or system, a study in the June 5 [2014] issue of the Cell Stem Cell shows that cycles of prolonged fasting not only protect against immune system damage — a major side effect of chemotherapy — but also induce immune system regeneration, shifting stem cells from a dormant state to a state of self-renewal.

 

The study has major implications for healthier aging, in which immune system decline contributes to increased susceptibility to disease as people age. By outlining how prolonged fasting cycles — periods of no food for two to four days at a time over the course of six months — kill older and damaged immune cells and generate new ones, the research also has implications for chemotherapy tolerance and for those with a wide range of immune system deficiencies, including autoimmunity disorders.

 

This tracks with fasting activating ISR and other conservation steps. Note: they call out that during the fast WC dropped - stop the fast if you get sick.

 

You however; seem to be shutting down some blood clotting factor / platelets; and, I see absolutely nothing to support what you are doing.

 

 

 

I just wonder if you stop to think about what you're saying. There is rank hypocrisy in the criticism. You are deciding to go from 3 grams fisetin to 3 grams of sublingual fisetin. Why? To increase bioavailability to get more bang for buck, to reach the senescent cells other doses didn't reach,, so you are well within the ballpark of the dosing I took.  More to the point, I didn't take it week by week.

 

Now consider the effects I observed:

 

1. Overnight cessation of at the time chronic histamine.

2. Nicked a wart while shaving, very slowly bled, not clotting 4 hours. A  few days alter normal clotting.

3. Arthritic knee increases substantially in weakness over several days, recovers, increased strength above baseline over weeks.

 

If I hadn't been suffering from excess histamine (I had no idea fisetin would treat it); the nightmare of nicking a wart when shaving; suffered from an artheritic knee. What would I have noticed? Nothing, save increased alertness.

 

Another member on the forum was taking high doses, iirc picked up a skin infection through swimming after high dosing on fisetin daily for months. The infection was extremely slow to heal requiring several courses of antibiotics. So he quit the high dosing.

 

His experience like mine was chance, the vulnerability is only expressed if it marries to an injury at the wrong time.

 

I have only ever noticed one instance of bleeding that was slow to heal since and that was maybe a few days after a 6g dose. It took perhaps  20 minutes rather 5 minutes to clot. I wouldn't have paid attention had it not been the previous instance.

 

GIven the doses you've taken have been around half that of the maximum I took, why would you assume there is not a risk for you? You are planning on taking the very doses you suggesting are "dangerous" when I take them and you're going sublingual, which as I have previously reported seemed to have a stronger impact on the knee (I noticed eye socket pain which I hadn't previously except perhaps during fasting). 

 

There was another forum member I believe noted the slowness of a wound to heal and stop taking the large doses. So that was three and you are right in the dosing range of all of us. But somehow it is prudent for you, but foolish for us - because a chance circumstance hasn't been exposed, you assume your dosing regime is safe for you?

 

You should be using these advanced party warnings to revise your judgement, rather than belligerently press on. What you are doing is far more dangerous given lost69's account of daily high dosing is a typical risk.  

 

I don't know what you want me to provide evidence of - that fasting is extremely beneficial and but tough? Likewise HIIT. No, that is a trivial and can be done yourself, the reported benefits of fasting are everywhere (Longo, Mattson, thousands of testimonies) and so are the accounts of at times extremely tough detox symptoms

 

I will provide one because it came from Sinclair in a recent interivew - the difficulty and the benefit of extended fasting:

 

 

nb you have reinvigorated the senolytics discussion and provided fresh content which is good, but behaving in an imperious way, assuming in yourself an authorative tone, lecturing on risk, while at the same time undertaking comparable protocols yourself, making unverifiable claims on safety, then you will antagonise. 

 

 

Edited by ambivalent, 18 January 2022 - 09:06 PM.

[DJSwarm]

[...]

 

Thanks again, DJSwarm. As to the beneficial effects of Rapamycin on stem cells: do you suggest a combination of for example of Rapamycin (or potentially Berberine, as seems to have your preference), with SC-removal may be 'more optimal'. And how would you suggest combining the two? 

 

I just found a publication that may be interesting with this regard: "Finally, rapamycin and other compounds have been demonstrated to have significant senotherapeutic effects (i.e. selective ability to restore or eliminate senescent cells) [5,6]. Many senotherapeutic drugs have minimal side effects and are effective with transient dosing. For example, at our clinic we routinely study the senotherapeutic drug fisetin, a phytonutrient with potent senolytic ability, and are conducing multiple randomized trials for its use in the context of osteoarthritis, an age-related pathology. Not only has rapamycin has been demonstrated to reduce senescence in MDSCs by our group [5], but others have demonstrated that blocking mTOR reduces stem cell senescence and associated secretory phenotypes [3,7]. In orthobiologic applications, the use of senotherapies like rapamycin is very compelling to reduce the anti-regenerative senescent profile of autologous stem cell therapies like bone marrow concentrate in various orthopedic indications." https://www.ncbi.nlm...les/PMC7467370/

 

 

It makes me wonder if one may not first start to use Rapamycin for a while (intermittent dosing seems common with this regard, as recommended by Dr. Green), before adding in the senolytics in a hit-and-run-fashion?

 

As to using liposomal Fisetin. I thought of simply mixing fisetin and Theaflavin with lecithin in a high speed blender. I remember a thread at Longecity where a patent was discussed that claimed that even without using ultrasonication this would result in the formation of liposomes. (Albeit I still have a ultrasonic cleaner I once bought for this purpose, but never used).

 

I know studies have confirmed bioperine could increase absorption, but could I ask how you came to the conclusion that bromalin may aid absorption?

And in case I missed it, were there any studies posted that confirm the senolytic properties of apigenin?

 

Sorry for the many questions, but do you suggest adjusting the dose of Fisetin and Theaflavin based on weight? (I also ask since my weight is about half of your weight).

 

I haven't done a run of Rapamycin yet. Frankly the reported side effects are as daunting as the benefits seem tempting. I'd read through the R thread and the papers I found on berberine as a sub are there as well.

 

Basically they found berberine had very similar effects to R in mice longevity (both natural and cancer prone). It is also a strong mTOR1 inhibitor but is more selective and doesn't seem to hit mTOR2 as hard. If I do a R run I'll probably do 7-9 mg once for the reset effect it has. Haven't decided. I might also do some fraction of that, boosted with berberine.

 

I saw bromalin was included in the quercetin I bought and found research on how it seems to improve absorption, possibly by increasing gut permeability. 

 

Fisetin seems dose dependent for senolytic effect. I might start at ~20mg/kg or 1500mg and see what you think before increasing. I've gone as high as 40mg/kg (3000mg).

 

Acute fisetin toxicity mice studies have gone as high as 2000mg/kg (16.6 grams for me, not recommended :P ) without any toxicity reported so there seems to be a good safety margin. I'm still looking into apigenin, though I've used smaller doses from time to time as a supplement. Theaflavin has less data on dosing but seems well tolerated and I've been targeting 1000-2000mg without issue.

[DJSwarm]

I just wonder if you stop to think about what you're saying. There is rank hypocrisy in the criticism. You are deciding to go from 3 grams fisetin to 3 grams of sublingual fisetin.

 

Never said squat about sublingual fisetin and I've said several times I was using liposomal fisetin 3000mg. My first fisetin run was 1200mg straight fisetin with oil, then when that batch ran out, 1500mg liposomal, then 3000mg liposomal. The absorption is so poor I doubt much of the first batch was absorbed. At least read what I say before getting all stuffy. 

 

I didn't take it week by week.

 

Neither did I, its all the other stuff you piled on until you started getting dangerous side effects which you pretend are part of the process that I'm calling out.

 

Now consider the effects I observed:

 

1. Overnight cessation of at the time chronic histamine.

2. Nicked a wart while shaving, very slowly bled, not clotting 4 hours. A  few days alter normal clotting.

3. Arthritic knee increases substantially in weakness over several days, recovers, increased strength above baseline over weeks.

 

Frankly I don't believe you on the histamine, diagnosis or treatment. 4 hours to clot over a number of days is dangerous. There is no reason that a senolytic run should increase knee weakness substantially.

 

I'm glad you recovered, but that doesn't negate the problems.

 

My cat is a firm believer in tough kitty love. None of his nicks bled or healed abnormally during any run.

 

If I hadn't been suffering from excess histamine (I had no idea fisetin would treat it); the nightmare of nicking a wart when shaving; suffered from an artheritic knee. What would I have noticed? Nothing, save increased alertness.

 

So what? Any strong blow to the head is likely to kill you with that clotting impairment.

 

Another member on the forum was taking high doses, iirc picked up a skin infection through swimming after high dosing on fisetin daily for months. The infection was extremely slow to heal requiring several courses of antibiotics. So he quit the high dosing.

 

Again, so what? Ignorance isn't a carte blanc. You are both lucky that it wasn't more serious and continuing at that would not be a good idea.

 

GIven the doses you've taken have been around half that of the maximum I took, why would you assume there is not a risk for you?

 

1) fisetin has been tested in large acute doses and not shown toxicity (2000mg/kg acute dose in mice). Chronic dosing, particularly high dose chronic administration does not seem to have the same safely profile.

 

2) I do a short 2-3 day run and take a minimum of 2 weeks off to let the dust settle and note effects. 

 

3) I've had zero side effects except for dasatinib which had its expected "mild flu-like" run down feeling. Wounds heal as expected. Blood test after the D+Q+F run was normal. No abnormal sickness.

 

4) I strongly suspect it is the other things in your stack having unexpected interactions and not the Fisetin per se, but you can bet I'll be very careful and look for verified reasons before pushing beyond this point.  

 

Testimonials are cheap, especially for something pushed as a pseudo religious practice. If it is so easy, show me the research. For example, there are numerous studies detailing the effects of meditation.

 

Not blog posts, not some guy justifying his practice, real research like the one I was finally able to find concerning stem cell renewal.

 

You know, like the piles of research showing intermittent fasting works or the piles of research showing "detox" is BS.

 

[ambivalent]

The stuff I piled on with it, you mean black pepper, olive oils and lecitithin to improve bioavailability? The very fact that I made it more bioavailable is what increased the risk through increasing the stem cell clearance - you know the same thing you're trying to do sublingually. For some unexplained reason you are assuming that the delayed wounding healing (a known effect of senolytics) has nothing to do with fisetin (a senolytic) but because of what was taken with it (which was designed to increase bioavaiablity).

 

Who said anything about fisetin toxicity? Why is that all you are concerned with measuring? I have told you that others have expereinced delayed healing while taking large doses of fisetin, but you want to pretend it hasn't happened. The issue isn't with toxicity but downstream effects of sensescent cell removal. Do you think that a study demonstrating non-toxicity of fisetin at high doses in anyway mittigates the risk of tumour growth through the removal of senescent cells? 

 

Honestly I am beginning to think all you can do is provide links, rather than deduce. No reason to see why seonyitics would weaken the knee? I've already given you one. There are a lot of senescent sells in arthritic joints, if they are removed rapidly en mass they will need to be replaced, which will take time. What do you think is going on if in the one place in the body they are abundant, there is pain immediately after taking a senolytic? You don't think it might have something to do with senescent cell clearance?

 

Let me make this very clear I have indulged you enough, I am not here to educate you out of your ignorance on fasting. There is both endless science and testimony, I linked it in the last post recent research quoted on chaperone mediated autophagy or are you doubting the scientific credentials of David SInclair?

 

And on Fisetin, saying that you doubt my reporting, is of breathtaking arrogance, I posted it several years ago, lying of course then for just this opportunity. I didn't take it to treat the histamine, but awoke with 90% clearance after months of quite a chronic problem after taking several grams the night before. I reported the effect and someone researched it and found a study, its probably in this thread; however, be a non-believer no more.

 

"These pharmacological actions of fisetin produce new suggestion that fisetin is a potential medicine for treatment of inflammatory diseases through the down-regulation of mast cell activation."

 

https://pubmed.ncbi....h.gov/17079162/

 

And as I have said, your comments about fasting are comprehensively misinformed, there is a ton of research, nobody in the field of aging doubts the value of fasting: De Grey, Sinclair, Mattson, Kenyon. Next to no one on this site doubts the benefit, yet somehow your instinct triumphs over all?

 

And more to the point, never dismiss testimonials, epsecially mass testimonials, on this site we use them in they go hand in hand with research. 

 

As I said I am not going to spend time doing your research for you, it will come to you in time how unwise your remarks on fasting have been, but here I will serve up one old bit of research:

 

https://news.usc.edu...ne system cells.

 

 

 

 

 

 

 

 

 

 

 

 

 

Edited by ambivalent, 19 January 2022 - 12:06 AM.

[DJSwarm]

Interesting: Melatonin Enhances the Anti-Tumor Effect of Fisetin by Inhibiting COX-2/iNOS and NF-κB/p300 Signaling Pathways

[DJSwarm]

 

As I said I am not going to spend time doing your research for you, it will come to you in time how unwise your remarks on fasting have been, but here I will serve up one old bit of research:

 

https://news.usc.edu...ne system cells.

 

So how long did it take you to find the article I already posted in #1022?

 

"There is some evidence that Fasting triggers stem cell regeneration of damaged, old immune system (Studying chemo patients)"

 

You obviously don't actually read anything so there is no point in trying to discuss anything further with you.

[ambivalent]

So how long did it take you to find the article I already posted in #1022?

 

"There is some evidence that Fasting triggers stem cell regeneration of damaged, old immune system (Studying chemo patients)"

 

You obviously don't actually read anything so there is no point in trying to discuss anything further with you.

 

Sound thinking. Do you think that is a likely explanation for posting the same link? And of course, it is a one I have posted before at longecity, so an unlikely coincidence. 

[Moondancer]

Let's bury the hatchet. We're all here with the same goal after all, and after several pages of quarrelling this doesn't seem to be very constructive any longer. 

Do we have any idea about the about the bioavailability of theaflavins? All studies I could find discussed the bioavailability of theaflavins from tea leaves not in an extract. 

[ambivalent]

Let's bury the hatchet. We're all here with the same goal after all......

 

Yes, a good idea.

[DJSwarm]

Let's bury the hatchet. We're all here with the same goal after all, and after several pages of quarrelling this doesn't seem to be very constructive any longer. 

Do we have any idea about the about the bioavailability of theaflavins? All studies I could find discussed the bioavailability of theaflavins from tea leaves not in an extract. 

 

Some that I've found poking around LE's site:

 

Han X, Zhang J, Xue X, et al. Theaflavin ameliorates ionizing radiation-induced hematopoietic injury via the NRF2 pathway. Free Radic Biol Med. 2017;113:59-70.

 

Noberini R, Koolpe M, Lamberto I, et al. Inhibition of Eph receptor-ephrin ligand interaction by tea polyphenols. Pharmacol Res. 2012;66(4):363-73.

 

Noberini R, Lamberto I, Pasquale EB. Targeting Eph receptors with peptides and small molecules: progress and challenges. Semin Cell Dev Biol. 2012;23(1):51-7.

 

Cameron AR, Anton S, Melville L, et al. Black tea polyphenols mimic insulin/insulin-like growth factor-1 signalling to the longevity factor FOXO1a. Aging Cell. 2008;7(1):69-77.

Caruana M, Vassallo N. Tea Polyphenols in Parkinson’s Disease. Adv Exp Med Biol. 2015;863:117-37.

 

Chen SQ, Wang ZS, Ma YX, et al. Neuroprotective Effects and Mechanisms of Tea Bioactive Components in Neurodegenerative Diseases. Molecules. 2018;23(3).

 

Peng C, Chan HY, Li YM, et al. Black tea theaflavins extend the lifespan of fruit flies. Exp Gerontol. 2009;44(12):773-83.

 

Aizawa T, Yamamoto A, Ueno T. Effect of oral theaflavin administration on body weight, fat, and muscle in healthy subjects: a randomized pilot study. Biosci Biotechnol Biochem. 2017;81(2):311-5.

 

Leone M, Zhai D, Sareth S, et al. Cancer prevention by tea polyphenols is linked to their direct inhibition of antiapoptotic Bcl-2-family proteins. Cancer Res. 2003 Dec 1;63(23):8118-21.

[Moondancer]

 

Some that I've found poking around LE's site:

 

Han X, Zhang J, Xue X, et al. Theaflavin ameliorates ionizing radiation-induced hematopoietic injury via the NRF2 pathway. Free Radic Biol Med. 2017;113:59-70.

 

Noberini R, Koolpe M, Lamberto I, et al. Inhibition of Eph receptor-ephrin ligand interaction by tea polyphenols. Pharmacol Res. 2012;66(4):363-73.

 

Noberini R, Lamberto I, Pasquale EB. Targeting Eph receptors with peptides and small molecules: progress and challenges. Semin Cell Dev Biol. 2012;23(1):51-7.

 

Cameron AR, Anton S, Melville L, et al. Black tea polyphenols mimic insulin/insulin-like growth factor-1 signalling to the longevity factor FOXO1a. Aging Cell. 2008;7(1):69-77.

Caruana M, Vassallo N. Tea Polyphenols in Parkinson’s Disease. Adv Exp Med Biol. 2015;863:117-37.

 

Chen SQ, Wang ZS, Ma YX, et al. Neuroprotective Effects and Mechanisms of Tea Bioactive Components in Neurodegenerative Diseases. Molecules. 2018;23(3).

 

Peng C, Chan HY, Li YM, et al. Black tea theaflavins extend the lifespan of fruit flies. Exp Gerontol. 2009;44(12):773-83.

 

Aizawa T, Yamamoto A, Ueno T. Effect of oral theaflavin administration on body weight, fat, and muscle in healthy subjects: a randomized pilot study. Biosci Biotechnol Biochem. 2017;81(2):311-5.

 

Leone M, Zhai D, Sareth S, et al. Cancer prevention by tea polyphenols is linked to their direct inhibition of antiapoptotic Bcl-2-family proteins. Cancer Res. 2003 Dec 1;63(23):8118-21.

 

 

 

Thanks a lot DJSwarm. It's unfortunate that most studies describing the (potential) effects of Theaflavins on the Bcl-2 proteins are in vitro studies. There doesn't seem to be evidence currently that theaflavins truly act as a senolytic agent in humans, am I mistaken? All the studies I found with Theaflavin are in vitro studies wherein cancer cell lines are treated with Theaflavins. I'm a bit disappointed Life Extension seems to make claims Theaflavins would act like a senolytic in humans solely based on this (meager) in vitro research, that doesn't tell us at all if and how Theaflavin in supplemental form would be able to selectively clear senescent cells in humans. This study at least does suggest Theaflavins may have senotherapeutic activity in rodents: 

https://www.cell.com...4131(20)30002-4

 

"Understanding the mechanisms of aging is important for developing strategies to combat the many chronic comorbidities associated with it. One of the causes of aging is the exhaustion of stem cells, including hypothalamic neural stem cells (htNSCs), because of their senescence. Here, Xiang-Hang Luo and colleagues investigate the role of a long non-coding RNA, termed Hnscr, which is highly expressed in htNSCs but decreases markedly with age. They found that Hnscr depletion is sufficient to cause senescence of these stem cells and aging-like phenotypes in mice. They also identified a natural small compound, theaflavin 3-gallate, which a key component of black tea, that mimics the action of Hnscr, and its use in mice greatly reduced the senescence of htNSCs while preventing aging-related physiological disorders."

Edited by Moondancer, 19 January 2022 - 08:53 PM.

[DJSwarm]

Thanks a lot DJSwarm. It's unfortunate that most studies describing the (potential) effects of Theaflavins on the Bcl-2 proteins are in vitro studies. There doesn't seem to be evidence currently that theaflavins truly act as a senolytic agent in humans, am I mistaken? All the studies I found with Theaflavin are in vitro studies wherein cancer cell lines are treated with Theaflavins. I'm a bit disappointed Life Extension seems to make claims Theaflavins would act like a senolytic in humans solely based on this (meager) in vitro research, that doesn't tell us at all if and how Theaflavin in supplemental form would be able to selectively clear senescent cells in humans. This study at least does suggest Theaflavins may have senotherapeutic activity in rodents: 

https://www.cell.com...4131(20)30002-4

 

"Understanding the mechanisms of aging is important for developing strategies to combat the many chronic comorbidities associated with it. One of the causes of aging is the exhaustion of stem cells, including hypothalamic neural stem cells (htNSCs), because of their senescence. Here, Xiang-Hang Luo and colleagues investigate the role of a long non-coding RNA, termed Hnscr, which is highly expressed in htNSCs but decreases markedly with age. They found that Hnscr depletion is sufficient to cause senescence of these stem cells and aging-like phenotypes in mice. They also identified a natural small compound, theaflavin 3-gallate, which a key component of black tea, that mimics the action of Hnscr, and its use in mice greatly reduced the senescence of htNSCs while preventing aging-related physiological disorders."

 

There isn't a lot but what there is tracks for it being a senolytic. In addition to the cancer studies, a couple more I was able to dig up...

 

Theaflavin 3, 3-Digallate Delays Ovarian Aging by Improving Oocyte Quality and Regulating Granulosa Cell Function

 

We found that TF3 could delay granulosa cell apoptosis in vitro and significantly reduce ROS-induced apoptosis and oxidative stress injury in the H2O2-induced oxidative stress model. Beta-galactosidase staining was performed on pGCs, KGN cells, and mouse periovarian adipose tissues cultured in vitro; the results suggested that TF3 treatment could delay the senescence of granulosa cells and periovarian adipose tissue. This indicates that TF3 can promote lysosomal degradation at the cellular and organism levels to facilitate the removal of senescent cells and harmful substances and effectively slow down the aging process.

 

Theaflavin-Enriched Fraction Stimulates Adipogenesis in Human Subcutaneous Fat Cells

 

Skin provides the first defense line against the environment while preserving physiological homeostasis. Subcutaneous tissues including fat depots that are important for maintaining skin structure and alleviating senescence are altered during aging. This study investigated whether theaflavin (TF) in green tea (GT) has skin rejuvenation effects. Specifically, we examined whether high ratio of TF contents can induce the subcutaneous adipogenesis supporting skin structure by modulating lipid metabolism.... TF-enriched CoF-GT fraction did not adversely affect hSCF cell viability but induced their adipogenic differentiation, as evidenced by LD formation, upregulation of adipogenesis-related genes, and adiponectin secretion. TF and TF-enriched CoF-GT fraction promoted differentiation of hSCFs and can therefore be used as an ingredient in rejuvenating agents.

 

Reducing Hypothalamic Stem Cell Senescence Protects against Aging-Associated Physiological Decline

 

Treatment of middle-aged mice with theaflavin 3-gallate reduced the senescence of htNSCs while improving aging-associated pathology. These results point to a mediator of the aging process and one that can be pharmacologically targeted to improve aging-related outcomes.

 

I've used it before with Quercetin and Fisetin and it seemed to be effective and without side effects.

[Moondancer]

Thanks DJSwarm. Please correct me if I'm wrong, but does for example the last study not indicate that TF would act like a senomorphic rather than as a senolytic? And how do we conclude from this study that using it in a hit-and-run fashion would result senescent cell clearance?

In the last study you cited they gave the rodents 8mg/kg Theaflavins daily for 6 months and noted: "Age-dependent loss of hypothalamic neural stem cells (htNSCs) is important for the pathological consequences of aging; however, it is unclear what drives the senescence of htNSCs. Here, we report that a long non-coding RNA, Hnscr, is abundantly expressed in the htNSCs of young mice but decreases markedly in middle-aged mice. We show that depletion of Hnscr is sufficient to drive the senescence of htNSCs and aging-like phenotypes in mice. Mechanistically, Hnscr binds to Y-box protein 1 (YB-1) to prevent its degradation and thus the attenuation of transcription of the senescence marker gene p16INK4A. Through molecular docking, we discovered that a naturally occurring small compound, theaflavin 3-gallate, can mimic the activity of Hnscr. Treatment of middle-aged mice with theaflavin 3-gallate reduced the senescence of htNSCs while improving aging-associated pathology."

 

The first study you posted also refers to potential senomorphic effects of Theaflavins, rather than senolytic effects. Which again, makes me wonder if and how we can conclude from that study that using it in a hit-and-run-fashion would result in senescent cell clearance.

 

Edited by Moondancer, 20 January 2022 - 07:03 PM.

[Moondancer]

I thought Vince Giuliano offers an interesting and different perspective on senolytics and why he feels SC's and SASP are critical for cell/tissue renewal: https://www.anti-agi...n-and-the-sasp/

It makes me reconsider how often we should do senolytic treatments. Perhaps once every year or every few years may be sufficient. Any more thoughts about this? 

 

As a sidenote: I assume the constant "off-topic's" are coming from someone that is discontent that we are discussing other potential senolytics in a topic about Fisetin. 

Fact is however that studies have shown that different senolytics can potentially target different types of senescent cells. Obviously with senolytic treatments we are trying to target different types of senescent cells, so combining Fisetin with other senolytics seems a reasonable approach and certainly worth discussion. 

Whether that could be Theaflavin or another compound, remains to be seen.  It's an approach for example LEF also follows in their 'Senolytic activator'.  It's a pity this apparently can't be discussed without people concluding it is 'off-topic'. Perhaps that person that is so keen on structurally hitting the 'off-topic' button may way want to contribute something useful about combining Fisetin with another senolytic to potentially target more types of senescent cells, or anything else constructive? Many thanks.

 

 

 

 

 

[Kentavr]

I thought Vince Giuliano offers an interesting and different perspective on senolytics and why he feels SC's and SASP are critical for cell/tissue renewal: https://www.anti-agi...n-and-the-sasp/
It makes me reconsider how often we should do senolytic treatments. Perhaps once every year or every few years may be sufficient. Any more thoughts about this?

As a sidenote: I assume the constant "off-topic's" are coming from someone that is discontent that we are discussing other potential senolytics in a topic about Fisetin.
Fact is however that studies have shown that different senolytics can potentially target different types of senescent cells. Obviously with senolytic treatments we are trying to target different types of senescent cells, so combining Fisetin with other senolytics seems a reasonable approach and certainly worth discussion.
Whether that could be Theaflavin or another compound, remains to be seen. It's an approach for example LEF also follows in their 'Senolytic activator'. It's a pity this apparently can't be discussed without people concluding it is 'off-topic'. Perhaps that person that is so keen on structurally hitting the 'off-topic' button may way want to contribute something useful about combining Fisetin with another senolytic to potentially target more types of senescent cells, or anything else constructive? Many thanks.

you can accept dietary supplement IP6.

[Woody42]

Over on our Senoleic section there is some talk of using fisetin combined with grape seed extract.

I tried 1 G of fisetin and 3 G of grape seed extract mixed with soy lecithin and olive oil. The following

day I felt almost like I had a hangover.                                                                                                           

 

   https://www.longecit...enescent-cells/

[DJSwarm]

Thanks DJSwarm. Please correct me if I'm wrong, but does for example the last study not indicate that TF would act like a senomorphic rather than as a senolytic? And how do we conclude from this study that using it in a hit-and-run fashion would result senescent cell clearance?

In the last study you cited they gave the rodents 8mg/kg Theaflavins daily for 6 months and noted: "Age-dependent loss of hypothalamic neural stem cells (htNSCs) is important for the pathological consequences of aging; however, it is unclear what drives the senescence of htNSCs. Here, we report that a long non-coding RNA, Hnscr, is abundantly expressed in the htNSCs of young mice but decreases markedly in middle-aged mice. We show that depletion of Hnscr is sufficient to drive the senescence of htNSCs and aging-like phenotypes in mice. Mechanistically, Hnscr binds to Y-box protein 1 (YB-1) to prevent its degradation and thus the attenuation of transcription of the senescence marker gene p16INK4A. Through molecular docking, we discovered that a naturally occurring small compound, theaflavin 3-gallate, can mimic the activity of Hnscr. Treatment of middle-aged mice with theaflavin 3-gallate reduced the senescence of htNSCs while improving aging-associated pathology."

 

The first study you posted also refers to potential senomorphic effects of Theaflavins, rather than senolytic effects. Which again, makes me wonder if and how we can conclude from that study that using it in a hit-and-run-fashion would result in senescent cell clearance.

 

I think you may be trying to split hairs here. In the first study they concluded: As a natural polyphenolic compound, TF3 could regulate mTOR to reduce ovarian metabolism to maintain the ovarian reserve, reduce the accumulation of ROS due to ATP overproduction, improve ovarian autophagy to remove aging substances, reduce ROS damage to oocytes and granulosa cells, delay female ovarian aging, and prolong female fertility.

 

They weren't specifically looking for apoptosis but improved autophagy, delaying female aging and prolonging female fertility is nothing to sneeze at. Like fisetin, it may well be both, with senomorphic more pronounced at lower doses and senolytic activity as the dose increases.

 

The second paper found that it renewed skin cells.

 

The third study

---

 

They also identified a natural small compound, theaflavin 3-gallate, which a key component of black tea, that mimics the action of Hnscr, and its use in mice greatly reduced the senescence of htNSCs while preventing aging-related physiological disorders.

...

 

Finally, we also assessed whether TF2A might have any obvious adverse effects. TF2A did not affect the body weight, blood cells, or blood biochemistry of mice (Figure S7F and Table S5). We also found that TF2A treatment did not result in appreciable cardiotoxicity, hepatotoxicity, spleen cell toxicity, pulmonary toxicity and nephrotoxicity (Figure S7G), nor cytotoxicity (Figure S7H). We also performed a tumorigenicity assay and found that TF2A treatment did not promote tumor development (Figure S7I). Thus, TF2A seems to be a relatively safe, naturally occurring compound.

---

 

So you certainly could mimic the study and dose continuously, but the majority of senolytic studies in humans have been a short run (2-3 days) on followed by a least the rest of the week off. Personally, I rather start there, as I've already done, and see if the long run is necessary, I did get positive results which seem lasting. So I'm working at avoiding continuously dosing anything as the body handles acute insults much better than chronic ones. YMMV, as they say.

[syr_]

After a lot of reading, I have decided to jump on the Fisetin bandwagon. Going for the bi-daily dosage, 200mg x2 for a few months to check the "other" effects.

[Moondancer]

Do we know how long it takes after taking (potential) senolytics, such as a high dose of Fisetin and Theaflavins, for senescent cells to get cleared out? 

Thanks in advance!

[Phoebus]

Fisetin turned this dude's hair from white to gray 

 

Pics at the link 

 

 

 

This was totally unexpected. I've been taking high dose (20mg-kg/day/4days/month) fisetin supplements for about 5 months now. A few days ago I noticed that my hair was getting darker again. My hair was almost pure white. Now it's a salt-and-pepper trending to just dark in the back with patches of grey. First picture is in 2019 (results of wife's haircut), second is a few days ago.

Also, my joints don't hurt quite so much as they used to.

I've been taking it for senescent cell removal and prevent mental deterioration.

 

https://www.reddit.c..._white_back_to/

[Advocatus Diaboli]

The 1-star reviews for the product used by the person in the link provided by Phoebus (post # 1043) may indicate that the product could be of questionable quality.

 

For example:

 

"Product packaging and design look professionally done however there is no information on the website about company ownership or any history of successfully operating in the nutritional supplement industry. There is no information on the website related to product COA (s) or where manufactured. All company registrations for the owner, an LLC registered in Deleware all happened in 2020. Though none of this means that the products sold by the company are not pure and potent and useful in the way that are described the lack of information and transparency in general when compared with more established nutritional supplement companies with long standing track records gives me pause about purchasing the product. If more information along the line of the type that I described becomes available I will reconsider a purchasing products from this company. For now I will pass."

 

 

 

[Moondancer]

Fisetin turned this dude's hair from white to gray 

 

Pics at the link 

 

 

 

https://www.reddit.c..._white_back_to/

 

It seems like an improvement. But the lightning in both pictures unfortunately is very different, which makes is difficult to draw any solid conclusions. You can also see how the color of his skin is different in both pictures. It's a pity its often difficult to obtain pictures taking in similar lightning, from similar angles etc. 

[ambivalent]

It seems like an improvement. But the lightning in both pictures unfortunately is very different, which makes is difficult to draw any solid conclusions. You can also see how the color of his skin is different in both pictures. It's a pity its often difficult to obtain pictures taking in similar lightning, from similar angles etc. 

 

Yes, if soneone said 'look how different the colour of my hair appears in these shots' we'd believe it, because we're used to seeing such weird effects - but still it is an impressive contrast and most likely true. I noted from one his comments:

 

"Something else I noticed; on the very first week I did the 2g-a-day-for-4-days all my old joint/tendon injuries (rotator cuff, achilles tendon, knees, feet) ached for a few days then faded out. Afterward I seemed to be in slightly less joint pain, but the difference could easily be just placebo effect."

 

This is similar and consistent to my reported experience with an arthritic knee. Oddly the other I in while hald asleep noticed pains in my hand, it was a frequent occurring experience over a decade ago and I wondered what had caused the reoccurrence,  too much sugar or alcohol perhaps  - my diet had not been great lately, but consistently so for some time. Then I remembered a couple of days previously I had taken 3gms of fisetin.

 

Also interesting to note the anecdote of his mother-in-law taking 500mg a day and seemingly improving alzheimers symptom.

 

 

[sensei]

Note: they call out that during the fast WC dropped

That's rather the point.

Prolonged Fasting (36+ hours) profoundly inhibits MTORC1/P3KI signaling, resulting in autophagy, some reduction in senescent cells, reduction in NLRP3 inflammasome, reduction in insulin, blood glucose, most inflammatory cytokines, profound reduction of WBC due to targeted autophagy of immune celks ---

and rejuvenation and proliferation of stem cells and regeneration of the immune system upon re-feeding.

There are a multitude of studies regarding the cellular effects of prolonged fasting due to MTOR1C inhibition, GTS.

[ambivalent]

I haven't seen this study reported, but it will be fascinating to see where it goes in light of Unity's ubx0101 fail on OA. My experiences with Fisetin, reported several times , led me to expect UBX0101 to succeed. Well, now it is Fisetin's turn. 

 

https://www.clinical...how/NCT04770064

 

Sadly they're not recruiting yet. The primary outcomes on safety though look comprehensive, if unexpected, though not discussed here: tumor lysis syndrome?

 

 

Primary

 

1. Change in markers of liver toxicity [ Time Frame: Change between baseline and 3-month follow-up ]
   The change in 2 markers of liver toxicity between baseline and 3-month follow-up will be assessed. Alanine amino transferase (ALT) and aspartate amino transferase (AST) are enzymes found mostly in the cells of the liver and kidney, and heart and liver, respectively. Both are useful tests for detecting liver damage.
2. Change in markers of kidney toxicity [ Time Frame: Change between baseline and 3-month follow-up ]
   The change in 2 markers of kidney toxicity between baseline and 3-month follow-up will be assessed. Blood urea nitrogen (BUN) is a waste product filtered out of the blood by the kidneys. As kidney function decreases, the BUN level rises. Creatine kinase (CK) is also an enzyme that is used to assess kidney function. Higher CK values are associated with greater burden on the kidneys.
3. Change in markers of tumor lysis syndrome [ Time Frame: Change between baseline and 3-month follow-up ]
   Tumor lysis syndrome is characterized by high blood potassium, low blood calcium, and high blood uric acid. The change in potassium, calcium and uric acid between baseline and 3-month follow-up will be assessed.

 

Secondary:

 

1. Pain Visual Analogue Scale (VAS) [ Time Frame: Change between baseline and 3-month follow-up ]
   The Pain VAS is a 100 mm scale where participants will be asked to report their level of pain over the past 24 hours, with 0 being associated with no pain and 100 mm being associated with the worst pain imaginable.
2. Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC) [ Time Frame: Change between baseline and 3-month follow-up ]
   The WOMAC is a 24-item instrument that has been found to be valid and responsive when quantifying changes in pain and function in individuals with knee osteoarthritis. Scores range from 0 to 96 with higher WOMAC scores being associated with worse pain, stiffness, and functional limitations.
3. Five times sit-to-stand test [ Time Frame: Change between baseline and 3-month follow-up ]
   The five-repetition sit-to-stand is commonly used to measure mobility and function in older adults. Participants are positioned in a standard 16" office chair with their arms at their sides and back located against the back of the chair. Participants are instructed to "Please stand up straight as quickly as you can 5 times, without stopping in between. Keep your arms folded across your chest. I'll be timing you with a stopwatch. Ready, begin." The test is timed using a stopwatch and the timer is stopped when the individual achieves a standing position on the 5th trial. Faster times are associated with less functional impairment.
4. Biomarker of cellular senescence (MMP-3) [ Time Frame: Change between baseline and 3-month follow-up ]
   Matrix metalloproteinase-3 (MMP-3) is commonly associated with senescence-associated secretory phenotype, and have been previously used to assess the mechanism of action of fisetin in human clinical trials. Greater serum concentrations of MMP-3 are associated with increased senescent cell activity.
5. Biomarker of cartilage breakdown (CTXII) [ Time Frame: Change between baseline and 3-month follow-up ]
   C-terminal crosslinked telopeptide type II collagen (CTXII) has been identified as a biomarker for the diagnosis, staging, and evaluating the prognosis of hip and knee osteoarthritis, and has also been demonstrated to be responsive over short testing periods (3 months). Greater concentrations are associated with increased cartilage breakdown. CTXII will be measured in the urine and will be normalized to creatinine level

 

[Moondancer]

It did not in the least surprise me ubx0101 failed. J. van Deursen several times sued a scientific reporter for defamation in Germany; so he had to remove his posts about Van Deursen. I'm not keen on making myself a potential target of a defamation suit. So I won't say more than that in his articles there were several comments also included of alleged members of Van Deursen's lab, with some claims about how the original study results allegedly came about. I assume citing a source is not defamatory, but this is the only source still available online that discusses a bit of the situation with Van Deursen (albeit not about those claims): https://www.postbull...-closes-his-lab

 

Edited by Moondancer, 19 February 2022 - 09:25 AM.

[ambivalent]

Well, I followed the Unity's stock at arms length and I can say there should have been a SEC investigation following UBX1010's fail. About a week before the announcement there was a dramatic inrease in volume, the price surged from aroun 8 or 9 to 15, then falling back to 12 or 13. The short volume revealed after trading was extremely high. It looked like an ambush. Most investors thought positive trial data had been leaked but it had all the hallmarks of a sting. Results were released, the stock fell to the mid 4s then over the next few sessions down to around $2.70. Then they ditched the OA drug and moved on to the eye-drugs phase 1 - a long.recovery. Incredibly though over the next few months the stock recovered, it quadrupled from its low on next to no news - beginning of phase 1, re-structuring the business etc. it in fact was higher than in the weeks and months before the ubx0101 fail. Then with the company recovering, some promising phase 1 readouts the stock fell back. From nearly 10 bucks to now below 1. 

 

Anyhow well off track, phase 1 data for UBX1325 appears promising..

 

https://ir.unitybiot...a-phase-1-study