1079 replies to this topic

[Martini]

I will try that! How much red wine did you add if i may ask?
 

 

sure, I added every day half a bottle of portuguese red wine to the mixture.
 

[stefan_001]

sure, I added every day half a bottle of portuguese red wine to the mixture.
 

 

thanks! I am going to try it at a glass level.
 

[Turnbuckle]

Two tablespoons of DMSO diluted in water works well too in my opinion.

 

DMSO is not the best solvent for oral use--

 

The ability of DMSO to damage neurons in dissociated cultures indicates that the toxicity likely results from a direct cellular effect. 

https://www.ncbi.nlm...les/PMC2682536/

 

 

 

A mixed ethanol/water solvent seems to very good for several flavonoids (better than ethanol alone), though I haven't seen data specifically for fisetin.

[Psy]

DMSO is not the best solvent for oral use--

 

 

Low-dose is OK in my opinion.

 

Lifespan extension in Caenorhabditis elegans by DMSO is dependent on sir-2.1 and daf-16.

https://www.ncbi.nlm.../?term=20828537

[Martini]

thanks! I am going to try it at a glass level.
 

 

will be interesting if you also notice any difference to the pure administration
 

[Turnbuckle]

Low-dose is OK in my opinion.

 

 

 

 

Then see this one --

 

Unexpected low-dose toxicity of the universal solvent DMSO.

 

Here, we demonstrate that DMSO induces retinal apoptosis in vivo at low concentrations (5 μl intravitreally dosed DMSO in rat from a stock concentration of 1, 2, 4, and 8% v/v)...These results highlight safety concerns of using low concentrations of DMSO as a solvent for in vivo administration and in biological assays. We recommend that methods other than DMSO are employed for solubilizing drugs...

 

 

 

Combine that with supplements that induce apoptosis and you might regret it.

Edited by Turnbuckle, 10 March 2019 - 01:03 PM.

[Martini]

Maybe this has something to do with it:
Oral administration of fisetin promotes the induction of hippocampal long-term potentiation in vivo - ScienceDirect

 

 

The study is interesting as it is done in vivo with rats. After oral administration the serum concentration of free Fisetin in rats is much lower than in mice. Rats serum concentration Cmax reach 12,2 ng/ml after oral administration of 50mg/kg compared to 69,34 ng/ml after oral administration of 10mg/kg in mice. (https://doi.org/10.1...phs.2017.12.008  and https://doi.org/10.1...44.2016.1245366)

It is mentioned that in in rats Fisetin in parent form could even be quantitated only in a few specimens with 50mg/kg administration. However even with 25mg/kg administration Fisetin crosses the blood-brain barrier and promotes synaptic functions in the hippocampus. This again supports the idea of other unknown pathways or metabolite activities as mentioned in my previous post.

 

[LarryG]

FYI....full disclosure first.  I have no science background and so, can easily misunderstand scientific studies.  However, I have been trying to digest info on making fisetin more absorbable.  One thing I noticed is that fisetin is poorly soluble in oil alone, so taking fish oil, etc, along with fisetin probably won't do the trick.  However, fisetin can easily be dissolved in a solution consisting of 90% water, 4% d-limolene oil, and 6% surfactant TWEEN 80 (polysorbate 80, a food additive), with gentle agitation (stirring).  Adding nisin, a food emulsifier, reduced particle size further, but nisin in small amounts is difficult to find, apparently, whereas polysorbate 80 or 40 are easy to find (don't use 20), as is d-limolene.  They can be bought on Ebay and elsewhere.  This emulsion can be consumed safely. 

 

Emulsifying fisetin...well, we don't actually have proof that this will improve absorption in humans.  However, there is a study showing, in mice, that a nanoemulsion of fisetin improved absorption 24 fold.  The article I am relying on about making nano emulsions was not about fisetin particularly, but about food grade emulsions generally.   We don't know anything about human absorption rates for emulsified fisetin so we can't, say, equate Xg of emulsified fisetin to 2g of raw fisetin, for instance.  The emulsification in the mouse study produced a particle size of about 153nm, whereas the above solution I posted creates a far smaller particle size, say, 40nm.

[QuestforLife]

The study is interesting as it is done in vivo with rats. After oral administration the serum concentration of free Fisetin in rats is much lower than in mice.

 

Probably not good news for bioavailability in humans, then.

[Oakman]

Probably not good news for bioavailability in humans, then.

 

Whatever the bioavailability of Fisetin is, apparently there is some bioavailability in humans, at least based on the responses of people in the forum and my own experiences. Whether those effects are actually senescence or something else is still an open question.

 

I just wish someone would do 'that study', so that we would know for sure. 'That study' would compare oral vs sublingual Fisetin and it synolytic abilities in humans, not rats or mice.

[Martini]

Probably not good news for bioavailability in humans, then.

 

not sure, as already in mice and rats the effectivness seems to be dependent on the metabolites. I think the open question is if in humans the metabolites have similar plasma concentration time profiles (see attachment and

https://doi.org/10.1021/jf802378q)

Attached Files

•  Plasma Concentration.JPG   40.85KB   0 downloads

[QuestforLife]

You might be right, Martini - as those are very similar molecules and conceivably could have similar effects.

 

[manofsan]

Hi - haven't posted in a long while...

 

So I've been trying out the Fisetin and finding it beneficial. I've read about savvy people taking it in episodic megadoses, but haven't gotten up the nerve to go that far. So far I've just used it here and there, but with good results each time.

 

What's the best way to maximize the permeation of the Fisetin throughout the body - are megadoses the only way? Even if you only do the occasional big dose, it wouldn't be productive to have the stuff interacting with the same narrow group of cells each time.

[ambivalent]

Then see this one --

 

 

 

Combine that with supplements that induce apoptosis and you might regret it.

 

 

Question on DSMO study: does it not seem reasonable that it is a calibration problem? DSMO encouraging apoptosis, will be beneficial to a point? I know of one forum member taking a teaspoon in a glass of juice daily. In addition Stanley Jacob seemed didn't appear suffer any cognitive decline, although it isn't clear if he self-medicated DMSO (working til 90, some dementia at his death in 91).

 

https://www.docgriff...O”-Passes-at-91
 

I've used Fisetin externally with DMSO and I'm pretty certain I experimented at least once with Fisetin+DMSO as a mouthwash at around 50:50 concentration with no noticeable ill effects. 

 

Still I shall be cautious, I will perhaps add a drop or two of DSMO, to the next round of 3-4 g of Fisetin I try.

 

[manofsan]

sure, I added every day half a bottle of portuguese red wine to the mixture.
 

 

Hi, what can help in improving the blood circulation to help the fisetin get better penetration to every nook and cranny of your bodily tissues?

Could alcohol help? Could nitroglycerine help?

 

Or is there something better?

[manofsan]

Wouldn't hurt to try, but the question is what is most responsible for skin aging?  The buildup of senescent cells, or the build up of advanced glycation end products (AGEs)? 

 

I think the conventional wisdom is that it is the latter, which a senolytic will not help.

 

Killing senescent cells AND a really good AGE breaker?  Sounds like we'd be on to something.

 

 

Waitasec - I thought that AGE's build up inside cells, helping to make them more senescent. So killing off senescent cells would purge their AGE's, no?

[Martini]

Hi, what can help in improving the blood circulation to help the fisetin get better penetration to every nook and cranny of your bodily tissues?

Could alcohol help? Could nitroglycerine help?

 

Or is there something better?

 

Manofsan, please see #445. At least from the regimen I have tried in the last 10 years, this one showed the strongest positive effects. However I guess that the differences in metabolism in different people could lead to other results.

[Krell]

FYI....full disclosure first.  I have no science background and so, can easily misunderstand scientific studies.  However, I have been trying to digest info on making fisetin more absorbable.  One thing I noticed is that fisetin is poorly soluble in oil alone, so taking fish oil, etc, along with fisetin probably won't do the trick.  However, fisetin can easily be dissolved in a solution consisting of 90% water, 4% d-limolene oil, and 6% surfactant TWEEN 80 (polysorbate 80, a food additive), with gentle agitation (stirring).  Adding nisin, a food emulsifier, reduced particle size further, but nisin in small amounts is difficult to find, apparently, whereas polysorbate 80 or 40 are easy to find (don't use 20), as is d-limolene.  They can be bought on Ebay and elsewhere.  This emulsion can be consumed safely. 

 

Emulsifying fisetin...well, we don't actually have proof that this will improve absorption in humans.  However, there is a study showing, in mice, that a nanoemulsion of fisetin improved absorption 24 fold.  The article I am relying on about making nano emulsions was not about fisetin particularly, but about food grade emulsions generally.   We don't know anything about human absorption rates for emulsified fisetin so we can't, say, equate Xg of emulsified fisetin to 2g of raw fisetin, for instance.  The emulsification in the mouse study produced a particle size of about 153nm, whereas the above solution I posted creates a far smaller particle size, say, 40nm.

 

Has anyone tried this? 

 

Any suggestions on amounts (by weight or volume?) required?  

 

Since I have a scale, how about these weights:

 

90 grams water

4 grams d-limolene - https://www.ebay.com/itm/131548129653

6 grams tween 80 - https://www.ebay.com/itm/302575005257

1.7 grams fisetin (83kg*20mg/kg=1.66gm) - https://www.amazon.c...uct/B0081NXW1C/

 

Does it make any difference in what order you mix them?

Edited by Krell, 15 March 2019 - 09:28 PM.

[manofsan]

Is there any such thing as a time-release version of Fisetin? Even if not currently available, could such a thing be possible? If so, then what would be the best way to formulate it?

 

Furthermore, what would be the best periodicity for the time-release to occur across? Should the duration of the time-release correspond to the regeneration time of the post-apoptosis cell population?

 

Wouldn't a time-release version of Fisetin be more useful than the regular stuff? Why or why not?

 

I'm grateful for any light you can shed on this.

Edited by manofsan, 15 March 2019 - 10:48 PM.

[Oakman]

Has anyone tried this? 

 

Any suggestions on amounts (by weight or volume?) required?  

 

Since I have a scale, how about these weights:

 

90 grams water

4 grams d-limolene - https://www.ebay.com/itm/131548129653

6 grams tween 80 - https://www.ebay.com/itm/302575005257

1.7 grams fisetin (83kg*20mg/kg=1.66gm) - https://www.amazon.c...uct/B0081NXW1C/

 

Does it make any difference in what order you mix them?

 

You might also put this in a cream base (less the water) and use on skin to see the result if any.

[manofsan]

So if the argument against overly frequent dosing of Fisetin is that it contributes to shortening of the telomeres, then shouldn't the same problem be caused by any senolytic - or even anything that encourages apoptosis, including exercise?

 

Shouldn't a person who always does a lot of exercise everyday then suffer faster shortening of their telomeres compared to a sedentary person who doesn't do any exercise at all?

(Note I'm not talking about all the general markers of health, I'm just talking purely about telomere length)

 

Edited by manofsan, 16 March 2019 - 01:45 AM.

[LarryG]

Krell, since I now have all the ingredients in hand, I am about to try this myself.  I never thought about the issue of weight vs volume.   I was just going to do it by volume.  Here's the article on making food grade nano emulsions generally, so perhaps you can decipher it and let us know.  https://onlinelibrar...1541-4337.12189

 

 

Edited by LarryG, 16 March 2019 - 03:07 PM.

[Martini]

 However, fisetin can easily be dissolved in a solution consisting of 90% water, 4% d-limolene oil, and 6% surfactant TWEEN 80 (polysorbate 80, a food additive), with gentle agitation (stirring).  Adding nisin, a food emulsifier, reduced particle size further, but nisin in small amounts is difficult to find, apparently, whereas polysorbate 80 or 40 are easy to find (don't use 20), as is d-limolene. 

Hi Larry,

where did you find this?

[LarryG]

Martini...it's within the body of this article posted here.  https://onlinelibrar...1541-4337.12189  It doesn't cover fisetin but rather, any food grade nano emulsion of an oil/water/surfactant mix. 

 

THIS article shows that fisetin absorption is improved by nano emulsion:   https://www.hal.inse...709735/document

 

In the latter study, using "Miglyol®812 N / Labrasol®/ Tween®80 / Lipoid E80®/ water(10%/10%/2.5%/1.2%/76.3%) =nano emulsion with an oil droplet diameter of 153 nm.  In the first study, it was shown that Tween 80/limonene/nisin with little agitation produced droplets of just 20nm, but that Tween 80 and limonene without nisin also made a nano emulsion.  There is a discussion also of how it gets mixed which I haven't digested yet.  But it seems that with the Tween 80 and limonene mix it may not be a problem since it apparently mixes easily without little agitation.  "In addition, the presence of some bioactive compounds may have minimal effect on particle size. A small increase in particle diameter was observed when nisin was added to a nanoemulsion made with 4% oil (D‐limonene) and 6% surfactant."  So, only a small increase with the added nisin.  Tween 80 and 40 are the best surfactants for particle diameter as Figure 6 shows.  Hence, 90% water, 4% D-limonene, and 6% Tween 40 as a formula for a nano emulsion of fisetin is my theory.

 

Edited by LarryG, 17 March 2019 - 02:55 AM.

[manofsan]

Hi all - would you recommend taking Fisetin before exercise or after? How much before, or how much after? Or what about taking it during the exercise, while it's going on?

[Martini]

Martini...it's within the body of this article posted here.  https://onlinelibrar...1541-4337.12189  It doesn't cover fisetin but rather, any food grade nano emulsion of an oil/water/surfactant mix. 

 

THIS article shows that fisetin absorption is improved by nano emulsion:   https://www.hal.inse...709735/document

 

 

Larry, I studied Quercetin for the microemulsification and found the following study https://doi.org/10.1...2249-017-0798-x.

As I believe Quercetin and Fisetin have similar chemical profiles, I think pepermint oil is an attractive candidate for solubility of Fisetin and could be used for skin administration as well as oral administration. Furthermore we could follow the self-microemulsifying formular used in the study also for Fisetin.

 

I attached the Quercetin solubility tab from the study.

Attached Files

•  Soluability Quercetin.JPG   54.29KB   0 downloads

[Krell]

Larry, I studied Quercetin for the microemulsification and found the following study https://doi.org/10.1...2249-017-0798-x.

As I believe Quercetin and Fisetin have similar chemical profiles, I think pepermint oil is an attractive candidate for solubility of Fisetin and could be used for skin administration as well as oral administration. Furthermore we could follow the self-microemulsifying formular used in the study also for Fisetin.

 

I attached the Quercetin solubility tab from the study.

 

Peppermint oil might be toxic for oral administration in the amount needed to dissolve a gram or more of fisetin.

 

https://www.ncbi.nlm...les/PMC3546250/

 

Edited by Krell, 17 March 2019 - 05:30 PM.

[manofsan]

Peppermint oil might be toxic for oral administration in the amount needed to dissolve a gram or more of fisetin.

 

https://www.ncbi.nlm...les/PMC3546250/

What about Limonene - is that toxic? I've heard it's sold as Food Grade / Dental Grade, etc.

 

Is the D-Limonene more toxic than than L-Limonene? ( I remember from university biochemistry that L-compounds are the safer ones, and that D-compounds are toxic.)

[Krell]

What about Limonene - is that toxic? I've heard it's sold as Food Grade / Dental Grade, etc.

 

Is the D-Limonene more toxic than than L-Limonene? ( I remember from university biochemistry that L-compounds are the safer ones, and that D-compounds are toxic.)

 

D-Limonene toxicity seems to be low

 

https://www.ncbi.nlm...pubmed/18072821

 

Altern Med Rev. 2007 Sep;12(3):259-64.

D-Limonene: safety and clinical applications.

Sun J¹.

 

Abstract

D-limonene is one of the most common terpenes in nature. It is a major constituent in several citrus oils (orange, lemon, mandarin, lime, and grapefruit). D-limonene is listed in the Code of Federal Regulations as generally recognized as safe (GRAS) for a flavoring agent and can be found in common food items such as fruit juices, soft drinks, baked goods, ice cream, and pudding. D-limonene is considered to have fairly low toxicity. It has been tested for carcinogenicity in mice and rats. Although initial results showed d-limonene increased the incidence of renal tubular tumors in male rats, female rats and mice in both genders showed no evidence of any tumor. Subsequent studies have determined how these tumors occur and established that d-limonene does not pose a mutagenic, carcinogenic, or nephrotoxic risk to humans. In humans, d-limonene has demonstrated low toxicity after single and repeated dosing for up to one year. Being a solvent of cholesterol, d-limonene has been used clinically to dissolve cholesterol-containing gallstones. Because of its gastric acid neutralizing effect and its support of normal peristalsis, it has also been used for relief of heartburn and gastroesophageal reflux (GERD). D-limonene has well-established chemopreventive activity against many types of cancer. Evidence from a phase I clinical trial demonstrated a partial response in a patient with breast cancer and stable disease for more than six months in three patients with colorectal cancer.

PMID: 18072821

[LarryG]

Manofsan: Wikipedia has a good article on limonene, d and l isomers.  D is what I have seen sold most often since it's used as a food flavoring.  L is said to smell like turpentine.  D is sold as a dietary supplement as you can tell by Googling it.  Life Extension sells Co-Q10 dissolved in D-limonene for improved absorption, and sells it in a 1000mg capsule by Jarrow and mentions it as a possible way of managing GERD.  As far as ingestion, "Taking into consideration conservative estimation, d-limonene appears to exert no serious risk for human exposure. Based on adverse effects and risk assessments, d-limonene may be regarded as a safe ingredient." (up to 250mg/kg daily tested in that case).  https://www.ncbi.nlm...ubmed/23573938 I have read of instances of taking 6gm a day.  However, on the skin it can be irritating, I would say as a concentrate.  I have used limonene cleaning products and they are very effective, and I think they contain l-limonene as that is one of the most common uses for it.  I can't find any reference to the use of l-limonene in food, though perhaps in cosmetics it is used.

 

Krell:  I would be hesitant to use a lot of peppermint oil orally, but on the skin I think it would be OK.  As to the limonene/Tween 40/fisetin/water mix on the skin, that would likely be fine but keep in mind that limonene can be irritating on the skin, but in my experience with limonene, it was irritating when used as a concentrate for cleaning and that was likely l-limonene, so I would want to test it on a small patch before using it on, say, my face.