1079 replies to this topic

[irk]

Would it be possible to use fistin (or another senolytic) to kill senescent cells in the skin by topical use? Anyone with a good idea or who even tried this?

 

I presume the dream is about skin rejuvenation. Thinking about this, one should note that skin is the target of the cosmetics industry, an old  business with turnover of hundreds of billions of dollars per year. Skin rejuvenation elixir would be a Holy Grail of this industry, a blockbuster worth gigantic amounts of money. Accordingly, a lot of money was poured into research throughout the history of cosmetics but with no progress in this direction. It is thus rather safe to assume that the result of applying fisetin, or any other compound intended for skin rejuvenation, will be an expensive urine and that to the satisfaction of those who made them.
 

Edited by irk, 28 February 2019 - 04:01 PM.

[Daniel Cooper]

Would it be possible to use fistin (or another senolytic) to kill senescent cells in the skin by topical use? Anyone with a good idea or who even tried this?

 

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.

[male_1978]

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.

 

This article (with paper reference) says that the senescent thing is quite important.

 

 

 

Moreover, the impact of senescent fibroblasts on skin pigmentation was directly demonstrated when eliminating senescent cells with an intervention that reduced pigmentation. Microneedle fractional radiofrequency (RF) is a cosmetic therapy that induces skin rejuvenation via electromagnetic thermal injury. The microneedle RF device was chosen to manipulate only dermal cells, in which the microneedles generate thermal coagulation columns in the dermis, not in the epidermis. It was previously demonstrated that fractional laser treatment decreases the occurrence of senescent fibroblasts in aged dermis. Ten volunteers with senile lentigo were treated with RF, and skin samples were collected from 4 participants who agreed to undergo a skin biopsy before and at 6 weeks after treatment. Following RF treatment, the number of senescent fibroblasts was significantly reduced. The elimination of these cells was thought to be caused by RF-induced cell death. The elimination of senescent fibroblasts from senile lentigo was accompanied by skin lightening.

 

https://www.fightagi...ency-treatment/

 

Its a completely different method (something with microneedles) but its about senescent cells (and btw. i am not saing that skin aging is ONLY from senescent cells).

 

Btw if you google for this skin rejuvenation method you get pretty nice before and after images. If this is the result of a senolytic effect, we should definitely discuss senolytic molecules in skin creams.

Edited by male_1978, 28 February 2019 - 05:28 PM.

[Florin]

I presume the dream is about skin rejuvenation. Thinking about this, one should note that skin is the target of the cosmetics industry, an old  business with turnover of hundreds of billions of dollars per year. Skin rejuvenation elixir would be a Holy Grail of this industry, a blockbuster worth gigantic amounts of money. Accordingly, a lot of money was poured into research throughout the history of cosmetics but with no progress in this direction. It is thus rather safe to assume that the result of applying fisetin, or any other compound intended for skin rejuvenation, will be an expensive urine and that to the satisfaction of those who made them.
 

 

Actually, Procter & Gamble and Unilever might be starting to sniff around the senolytics/skin aging space.

 

Targeting Senescence-Specific Apoptosis Resistance Genes for the Clearance of Senescent Cells in 2D and 3D Human Models
https://gtr.ukri.org...ef=BB/P002579/1

 

Evaluation of Senolytic Interventions in Skin Ageing
https://gtr.ukri.org...per.pro.t&type=

[Daniel Cooper]

This article (with paper reference) says that the senescent thing is quite important.

 

 

 

 

https://www.fightagi...ency-treatment/

 

 

 

It says that cell senescence is importing wrt age spots.  I don't doubt that a bit.  But age spots normally develop long after the first signs of skin aging - wrinkles, sagging, and a loss of elasticity.  Those attributes of aging skin seem to be mainly driven by the formation of advance glycation end products.

 

I don't doubt that removing senescent cells from the skin is a good thing, but without removing AGEs you aren't ever going to really roll back the clock on skin aging. Ideally, you'd want to do both.

Edited by Daniel Cooper, 28 February 2019 - 06:29 PM.

[QuestforLife]

It says that cell senescence is importing wrt age spots. I don't doubt that a bit. But age spots normally develop long after the first signs of skin aging - wrinkles, sagging, and a loss of elasticity. Those attributes of aging skin seem to be mainly driven by the formation of advance glycation end products.

I don't doubt that removing senescent cells from the skin is a good thing, but without removing AGEs you aren't ever going to really roll back the clock on skin aging. Ideally, you'd want to do both.

I don't buy that AGEs are the main reason for skin aging - after all if you have pale skin your skin ages (wrinkles, pigmentation, dryness, etc.) 10-20 years earlier than those with dark skin - that demonstrates that it's damage from UV that is primary, presumably via ROS and inflammation, and the exact same thing happens to those with dark skin, only later, presumably because of slower turnover (damage from UV is less)- and we also know that skin turnover declines with age, AND most of the 'treatments', i.e. chemical peels, retin A, derma rolling, work (to some limited degree) because they force the skin to turnover more quickly. So this implicates telomere loss from cellular turnover and cellular senescence.

Just my opinion of course but the logic seems sound to me. The issue of how to get a treatment into the skin is another matter - given the skin is intended to keep stuff out, delivery via the bloodstream might be the best way to go.

[ambivalent]

I used fisetin with DMSO once, possibly twice. I was impressed with the sense of exfoliation, most notably on my forehead (I rarely exfoliate). However, I was concerned that I may have lost some facial mass. I also put the DMSO + fisetin on one hand. I didn't notice a difference in smoothness, a friend, though, on a spot-the-difference invitation, thought the non-treated hand looked 'more swollen' than the other, which I perhaps rather unbiasedly agree.

 

As for the cosmetic industry's failed investment rendering any amateur attempts futile, that is simply not true. Like drug companies they want treatments not solutions. And besides these senolytics haven't knowingly been an option for skin care until recently. 

 

I've certainly felt the difference in skin, but can't say I've noticed itvisually. Lost69, though, has and he has been on stem cell/senolytic protocols quite rigorously. I would suggest going for a small patch of skin perhaps on the forehead and treating DMSO+fisetin for a few weeks. The smell, though, can be a problem for others.

Edited by ambivalent, 28 February 2019 - 09:24 PM.

[Martini]

Fisetin metabolites: someone suggested that these might have senolytic activity. Remember, the original basis for looking at fisetin was in vitro evidence that the unmetabolized parent molecule had substantial senolytic activity in vitro: it would be very suprising if the detoxification products — which are formed, exactly, to chemically castrate them and ensure their rapid removal from the circualtion — had similar activity.

 

Fisetin metabolites: Geradol is one of the metabolites of Fisetin showing strong in vivo anticancer activities. Basically I doubt that Fisetin itself can lead to the the senolytic results in vivo as the plasma concentration decline biphasically with a rapid half-life of 0.09 h.


 

Edited by Michael, 03 March 2019 - 08:59 PM.
trim quote

[LarryG]

First, it makes all the difference when you have a really knowledgeable mod as we do.  Now, as to skin.  I'm 74.  I'm removing age spots on my face and hands hydroquinone, which is said to be a bleaching agent, at 3% level, which takes quite some time but is safer than higher levels.  Never the less, the skin is very wrinkled, far beyond any other skin.   I spent a lot of time in the sun, and my hands were by far the most exposed to the sun.  So, I assume that whatever the sun does to skin by way of damage is what would have to be undone.  This isn't a high priority to me but it is to a lot of people.  I removed a sort of plaque on my forearm by freezing (Wart-X) just for the heck of it.  It destroyed the plaque and skin, then healed without a scar, but that's not terribly practical to take a chance like that on a conspicuous spot.  So, if anyone wants me to experiment on a hand with some formulation, I'll be glad to do it, within reason, of course.  It would seem that a safe chemical peel or exfoliation, removing damaged skin, might work.  Would skin damaged by the sun be senescent?

[irk]

As for the cosmetic industry's failed investment rendering any amateur attempts futile, that is simply not true. Like drug companies they want treatments not solutions. And besides these senolytics haven't knowingly been an option for skin care until recently.

 

Amateur attempts or professional attempts, rejuvenation by a simple magic compound is unlikely. Fisetin case is simple to illustrate of this claim as this is natural compound available in small, but in non-negligible amounts in strawberries. Cosmetics industry has investigated every possible plant and extracts from them for their effects on skin. One can be certain that they looked for any type of berry on Earth and extracts from them. They have not needed to investigate fisetin per se, if there would be slightest real effect on the skin from an extract they would look in great detail what is responsible for it. They know that the stuff like vitamin E makes skin looking better and they use it massively.

 

Now, skin rejuvenation is theoretically not excluded due to the existence of mechanism  of partial resetting of the clock of stem cells and growing the new cells from them. But this is an entirely different ball game with tons of potential side effects looming. 
 

[ambivalent]

This is simply untrue - for one only a absurdly small percentage of plants have been researched. How long has garlic been around? 

 

https://www.mdpi.com...049/21/1/70/htm

 

And how much cosmetic researching investigating DMSO as a vehicle?  Anyhow, this is O/T.  

 

 

 

 

 

[irk]

This is simply untrue - for one only a absurdly small percentage of plants have been researched. How long has garlic been around? 

https://www.mdpi.com...049/21/1/70/htm

 

This illustrates well the problem: they made tests on h a i r l e s s  m i c e  providing diet with supplementation of garlic powder and claiming photoaging was ameliorating. Garlic is obviously not a part of standard mice diet and the effect described could be real. But how this might be relevant to humans? Garlic is a part of human diet from a long time and in some cultures it is consumed in substantial amounts. Any skin rejuvenation effect would be already noticed. What is reported in this paper is pure academic research. It is often so that not only research results do not translate from laboratory mice to humans, they do not translate even from lab mice to wild mice since mice used in laboratory are special genetically pure strains. 

 

Cosmetics industry is in constant hunt for new compounds, rejuvenating compound would be a blockbuster. Ii is unlikely extracts from something so easily available as strawberries and berries in general were not investigated for its potential cosmetic effects.

 

About killing senescent cells, their full role is by far unknown, it is known that they have some role in wound healing, they could have a role e.g. in cancer prevention. Overall assuming they play only a bad guy role seems simplistic. In an aged skin excessive number senescent cells could be due to some processes going haywire or an organism using them as a last line of defense against developing cancer. Killing senescent cells may thus risk that a small scratch would heal with difficulty or risk of skin cancer would be elevated. We simply do not know.

[LarryG]

I'm looking to improve on the poor absorption of fisetin, so I've read up on two things....what is a good solvent, and what is a good emulsifier (to reduce particle size).  For those of us who have been using oil to try to improve absorption, I'm afraid that according to my reading, this doesn't do a lot of good.  I just read that oil of any kind, alone, is a poor solvent, >5%.  However, fortunately, the issue has been researched by others more learned, and some conclusions about what works can be reliably found.  Some solvent/emulsifier combination make for large particles, some for small or very small.  Some require careful heating, some require strong shaking.  But some don't require any of that, and produce very fine particles (micro emulsion).  Keep in mind, I have NO science background.  Within this study is a chart which I hope our more knowledgeable mod can decipher (table 7).  It appears that a combination of d-limonene (an oil from citrus) plus nisin (food ingredient) for a solvent, plus Tween 80 (polysorbate 80) produce a particle size of 20nm with only gentle agitation.  Now, two questions....first, does this mean it's likely much more absorbable?  Second, how safe is Tween 80?  I know it's used as a food and cosmetic additive.  Here's the article:  https://onlinelibrar...1541-4337.12189

[Michael]

Fisetin metabolites: Geradol is one of the metabolites of Fisetin showing strong in vivo anticancer activities [emphasis added]. Basically I doubt that Fisetin itself can lead to the the senolytic results in vivo as the plasma concentration decline biphasically with a rapid half-life of 0.09 h.

 

Three things.

 

First, can you cite a study finding what you say bolded above? (Always best to proactively back up assertions with citations, BTW). I dug around some and could find no supporting evidence: the closest thing was a summary of earlier research in PMID: 27163728, citing PMIDs 21840301 and 19090755, neither of which actually finds this.

 

Second: suppose, for the sake of argument, that geradol indeed exerted potent in vivo anticancer activity. That doesn't at all demonstrate that it will exert potent senolytic activity. Indeed, one of the standard means of inducing senescence involve exposing cells to a range of DNA-damaging chemotherapeutic agents, and patients treated with such agents suffer a burden of excess senescent cells that seems to predict poor future outcomes — poor outcomes that are, in mice, ameliorated exactly by senolytic therapy (eg. PMID 27979832).

 

And third: Martini and everyone: please remember to trim quoted material to just the portion of the original post that you're addressing: leaving a whole post that is 80% irrelevant to what you're addressing slows loading speeds and generates a lot of false positives when using a site search.

[xEva]

I used fisetin with DMSO once, possibly twice. I was impressed with the sense of exfoliation, most notably on my forehead (I rarely exfoliate).

 

 

DMSO by itself will exfoliate, coz it's very drying to the skin, especially full strength. To know for sure, you could use just 'a vehicle' on a patch, for comparison with vehicle+fisetin.

[male_1978]

I found these experiments with fisetin on skin cells:

 

...a novel role of fisetin in skin health via downregulation of melanosis and adipogenesis, and upregulation of skin fibril-related genes was shown herein.

 

Regarding wrinkels:

... excessive accumulation of fat can be a cause of subcutaneous cellulite that causes wrinkles in skin (22).

 

https://www.ncbi.nlm...Article_110.pdf

 

Is there a connection to the senolytic activity? I dont know.

[Martini]

First, can you cite a study finding what you say bolded above? (Always best to proactively back up assertions with citations, BTW). I dug around some and could find no supporting evidence: the closest thing was a summary of earlier research in PMID: 27163728, citing PMIDs 21840301 and 19090755, neither of which actually finds this.

 

 

Michael, I think it is fruitful to discuss the action of the metabolites in connection with the in vivo mice results, especially under this topic.

Coming back to the study “Fisetin is a senotherapeutic that extends health and lifespan” I found the following results surprising:

The diet studies with a daily feed of 60mg/kg led to a reduction of senescence markers in multiple organs. Assuming the mice were eating three meals per day one can calculate with 20 mg/kg of oral administration to estimate the peak Fisetin plasma concentration.  According to the results of (https://doi.org/10.1080/10717544.2016.1245366) it should be reasonable to estimate a peak plasma concentration of about 140 ng/ml three times daily with a first rapid alpha half-life of 0.09 h (5.4 min), followed by a longer terminal disposition half-life beta of 3.12 h (doi:10.1016/j.bcp.2011.07.097).
Following these data the Fisetin plasma concentration in the daily feed would fall to a level of about 70 ng/ml after 5.4 min.

 

Looking into the in vitro analysis of Fisetin I found the following:

The lowest concentration thresholds for any senolytic activity for HUVECs in vitro of Fisetin is 500 ng/ml with three days exposure, but the main activities are in the range of several µg/ml (http://doi.org/10.18632/aging.101202). Obviously there are much lower plasma concentrations in vivo than needed to activate any senolytic activity.

The second mode of Fisetin administration in the study reveals again surprising results. Here the mice were treated with 100 mg/kg Fisetin for 5 consecutive days by oral gavage, or vehicle. So there was only one daily peak with a first rapid alpha half-life of 0.09 h (5.4 min), followed by a longer terminal disposition half-life beta of 3.12 h. Looking at available study data for the peak plasma concentrations we can assume between 700 ng/ml and  below 1 µg/ml (based on https://doi.org/10.1...247.2013.860131 and https://doi.org/10.1...247.2013.860131). Again these concentrations seem to be too low to meet the in vitro threshold data mentioned before.

 

Summarizing these considerations suggest that it is difficult to infer the in vivo effects from their in vitro activities.

Based on these findings I believe that the metabolites should play an important role in the senolytic activities.

A second mechanism could be the following:

However,ß-glucuronidase was found to be present in liver and increasingly released by neutrophils at inflammation sites (28, 29). Therefore, deglucuronidation might occur in various tissues, resulting in the formation of flavonoid aglycones, which warrant further studies

→ source (external link)

Coming back to the start of the considerations you stated “it would be very suprising if the detoxification products — which are formed, exactly, to chemically castrate them and ensure their rapid removal from the circualtion — had similar activity.” Can you cite a study finding what you mentioned above?

If this is true the only left explanation for the in vivo senolytic results are deglucuronidation activities in the tissues where Fisetin showed senolytic activities.

 

Following the rationale above I think it is reasonable to assume that even in humans with the stronger metabolism oral Fisetin administration could lead to senolytic activities.

[stefan_001]

@martini you may be interested in this paper:

In conclusion, a convincible four-step strategy and various
postacquiring data mining tools of UHPLC-Q-TOF-MS/MS
were successfully explored for identification of the metabolites
of fisetin in vitro and in vivo. The results showed that 53
metabolites in vivo (18 from the blood, 49 from the urine,
34 from the bile, and 34 from the faeces) and 14 metabolites
in vitro were detected. From view of the metabolism of
fisetin, the reactions of oxidation and loss of oxygen were
the basis for other metabolic reactions, which contained
methylation, hydrogenation, sulfation, and glucuronidation.

 

https://pubs.acs.org...s.jafc.7b04265#

Edited by stefan_001, 05 March 2019 - 08:40 PM.

[ambivalent]

DMSO by itself will exfoliate, coz it's very drying to the skin, especially full strength. To know for sure, you could use just 'a vehicle' on a patch, for comparison with vehicle+fisetin.

 

 I used DMSO first topically with fisetin, but subsequently with a couple of other agents and the effect was certainly different but obviously it isn't a well controlled observation - I will try it again at some point. 

 

The other hand had been exposed to DMSO, not DMSO plus Fisetin and there was still a noticeable difference between the two - but that as now receded as I've been taking high doses of collagen + HA which has also plumped up my face a little.

[ambivalent]

DMSO by itself will exfoliate, coz it's very drying to the skin, especially full strength. To know for sure, you could use just 'a vehicle' on a patch, for comparison with vehicle+fisetin.

 

 I used DMSO first topically with fisetin, but subsequently with a couple of other agents and the effect was certainly different but obviously it isn't a well controlled observation - I will try it again at some point. 

 

The other hand had been exposed to DMSO, not DMSO plus Fisetin and there was still a noticeable difference between the two - but that has now receded as I've been taking high doses of collagen + HA which has also plumped up my face a little.

Edited by ambivalent, 06 March 2019 - 12:32 AM.

[ambivalent]

Can someone delete the second post, even if that means losing a rare 'well researched' accolade: I'm almost tempted to trade in the two likes for it.

[chris1299]

Hi, sorry for being late to this thread. I've done two self experiments with fisetin from "Doctor's Best", using 1.5 grams/day for five days the first time, then 3 grams/day for five days the second time. No noticeable effect. I'm looking to up dosage for a third try, but want to switch my source. I found this: https://www.alibaba....25-fisetin.html

Does anyone know if any of the sources on that site are reliable, or have some other reliable source that is cheaper than Doctor's Best/other easily available pill forms?

[William Sterog]

I get a really strange effect from Fisetin. I notice nothing when I take it, maybe a very mild antiandrogenic effect as mentioned earlier, but the day after, my mind works extremely well. I feel my brain working worse and worse every year, and I'm just 26, fuck, but the day after taking a dose of Fisetin I get all my functions back, measurably. It is pretty remarkable. Obviously, I don't think that this happens because of any senolytic effect, but for an anti-inflammatory mechanism.

[irk]

I get a really strange effect from Fisetin. I notice nothing when I take it, maybe a very mild antiandrogenic effect as mentioned earlier, but the day after, my mind works extremely well. I feel my brain working worse and worse every year, and I'm just 26, fuck, but the day after taking a dose of Fisetin I get all my functions back, measurably. It is pretty remarkable. Obviously, I don't think that this happens because of any senolytic effect, but for an anti-inflammatory mechanism.

 

In your case impact of placebo effect might be significant, perhaps decisive. One should try to eliminate the impact of placebo by making randomized blind experiment with identical looking tablets without Fisetin. This of course is a wider problem than Fisetin. But how to get such tablets? It leads to a business idea: For any supplement package/tablets claiming something there should be an identical looking package/tablets with no supplement.
 

Edited by irk, 07 March 2019 - 09:55 AM.

[Martini]

For the fourth time I have tried my regimen from my post on 14 February 2019 - 10:37 AM.

It is again showing very strong effects during the two days of administration. My osteoarthritis improved a lot and I am planning to reduce the frequency to every three months from now on.

As I had different Fisetin approaches before I think the gain in efficiency came from the red wine I added. The rational was the following study for quercetin (https://doi.org/10.1...sj.bjp.0706662)

The goal was to channel the Fisetin metabolism towards O-methylation. It would be interesting to know if anybody has tried red wine in combination with Fisetin or would like to try it.

[Psy]

For the fourth time I have tried my regimen from my post on 14 February 2019 - 10:37 AM.

It is again showing very strong effects during the two days of administration. My osteoarthritis improved a lot and I am planning to reduce the frequency to every three months from now on.

As I had different Fisetin approaches before I think the gain in efficiency came from the red wine I added. The rational was the following study for quercetin (https://doi.org/10.1...sj.bjp.0706662)

The goal was to channel the Fisetin metabolism towards O-methylation. It would be interesting to know if anybody has tried red wine in combination with Fisetin or would like to try it.

 

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

Edited by Psy, 08 March 2019 - 03:01 AM.

[William Sterog]

In your case impact of placebo effect might be significant, perhaps decisive. One should try to eliminate the impact of placebo by making randomized blind experiment with identical looking tablets without Fisetin. This of course is a wider problem than Fisetin. But how to get such tablets? It leads to a business idea: For any supplement package/tablets claiming something there should be an identical looking package/tablets with no supplement.

Of course. Placebo can't be ruled out. Or maybe is because of other intervention. But I have tried hundreds of supplements, and I feel absolutely nothing from most. For example, I was very hyped with Mag-L-Threonate, and I feel no benefits from it. A little hypoglycemia at best is what I get. Also, I didn't know why I was so intelligent on mondays, I think that it is because I take Fisetin on Sundays, but who knows. Just my little report.

[Dstein]

I get a really strange effect from Fisetin. I notice nothing when I take it, maybe a very mild antiandrogenic effect as mentioned earlier, but the day after, my mind works extremely well. I feel my brain working worse and worse every year, and I'm just 26, fuck, but the day after taking a dose of Fisetin I get all my functions back, measurably. It is pretty remarkable. Obviously, I don't think that this happens because of any senolytic effect, but for an anti-inflammatory mechanism.

 

How much do you take and do you add something to help bioavailability?

[stefan_001]

For the fourth time I have tried my regimen from my post on 14 February 2019 - 10:37 AM.

It is again showing very strong effects during the two days of administration. My osteoarthritis improved a lot and I am planning to reduce the frequency to every three months from now on.

As I had different Fisetin approaches before I think the gain in efficiency came from the red wine I added. The rational was the following study for quercetin (https://doi.org/10.1...sj.bjp.0706662)

The goal was to channel the Fisetin metabolism towards O-methylation. It would be interesting to know if anybody has tried red wine in combination with Fisetin or would like to try it.

 

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

[Dstein]

... , but the day after, my mind works extremely well. I feel my brain working worse and worse every year, and I'm just 26, fuck, but the day after taking a dose of Fisetin I get all my functions back, measurably. It is pretty remarkable. Obviously, I don't think that this happens because of any senolytic effect, but for an anti-inflammatory mechanism.

 

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