Fisetin to Clear Senescent Cells

Dan Nave 

Hi Dan! How are you doing?

Regarding curcumin and its role as anti-ageing agent. Senolytic or not?

I read this article and I like to share it. There are groups promoting curcumin as a senolytic agent. But here curcumin is not seen as a primary senolytic agent but as a geroprotector. Quite a lot of in vivo studies and the salk institute chose curcumin and fisetin as the two most promising natural geroneuroprotectors. 

https://www.researchgate.net/publication/328925429_Geroneuroprotectors_Effective_Geroprotectors_for_the_Brain

https://www.genengnews.com/news/life-extending-alzheimers-disease-candidates-identified-from-diet-supplements/

Curcumin is fascinating. I read  another article and it made me think about the importance of optimum dosing. Under the section "6 conclusion" they illustrate the  importance to find the optimal dose of curcumin. To much curcumin could be detrimental. 

https://www.mdpi.com/1422-0067/20/5/1239/htm

They also write that curcumin, as anti-ageing intervention, might work through AMPK induction. 

"it is possible that positive effects of curcumin supplementation, observed on the organismal level, can be attributed to sirtuin and AMPK induction rather than the inhibition of cellular senescence"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991376/

Bottomline: Is curcumin a senolytic substance?  we don't know. But there is a growing amount of indications that it is a promising anti-ageing agent. 

Best Regards. 

Staffan Olsson Just curious what you guys think about mixing the fisetin with water and swallowing then adding an olive oil chaser.  Do you think this is the same as mixing it beforehand before consuming?

JOHN 

I have tried several ways to administer fisetin. I have mixed fiestin in the same way as they did with rats in the el mayo study, I have used home made rectal suppositories, I have mixed fisetin with oils like olive oil and avocado oil.

So far my subjective experience is that the most important (for me) has been to take fisetin with some piperine or  with some piperlungumine + piperine.

I have also taken fisetin without oil and then the experience has been approximately the same as when I take fisetin with oil.

So the jury is out there. But if you use piperine/black pepper and add some oil. And maybe also add some curcumin, then you are doing it in a way that is in line with my best self experiments.

It is very hard to find out which way is the best way to take fiestin. The most convincing study has been on animals and Intraperitoneal injections. But that I will not do.

Staffan Olsson thank you. I have been taking with olive oil and piperine. I usually would mix them altogether but this last time I drank it mixed with water and did 3 ounce shot of olive oil afterwards. The question is does it absorb differently if it doesn't all hit the stomach mixed together. It may be a stupid question since it is all going to the stomach within seconds of each other. 

JGC this is now available at Alive By Nature - liposomal Fisetin. I just ordered some. The dosing seems a bit low, but the claims is it is 3-4 x (or more) bioavailable.

https://alivebynature.com/product/lsg-fisetin-liposomal-sublingual-gel/

Simone Maher Really interesting - first I had heard of this product. If it works, the extra $ would be worth it. Please let us know your experience! Are you still using a dose of 20 mg/kg?

JGC It's 75 mg per serving, and 60 servings per bottle = 4.5 grams

Jacques Mathieu

I think JC is right. Here is the label:

• 75 mg Fisetin (98% pure) per serving
• 1 serving = 2 pumps = 2 mL
• 60 servings per bottle

I have not actually tried Fisetin yet. I have been doing a lot of research on senolytics and it seemed to me to be a better choice than D+Q due to research, cost, availability etc. My thought is to try this in addition to the powder form to get me to the 20 mg/Kg 2 day dose. There does seem to be a lot of debate over absorption and dosage. See this link ( https://alivebynature.com/forums/viewtopic.php?f=45&t=1881)

It's not that $ to use both the achieve the total, and I like that this form may be better absorbed. I plan to do this twice a year, in addition to using FOXO4-DRI peptide and anything else I can read up on/try.

My only experience thus far with senolytics is with Life Exension Senolytic Activator. Can't say I have felt any difference there, but I understand some changes happen slowly over time and there probably won't be a blockbuster effect. I am 44, and really only got into health as a way of solving my horrible insomnia. I am thinking of this as  preventative strategy to be used over time vs. trying to solve some current ailment.

Thanks to everyone for sharing your methods and sources, I'm definitely going to try the powder with the olive oil. Would never have thought of that had I not read it here!

Simone Maher 

Argh! Math/measurements is not my strong suit. Now, re looking at it I think you are right Jacques Mathieu . It does say 75 mg per serving, not 75 mg in the whole bottle.  Whew! :)

Simone Maher Jacques Mathieu That 4x bioavailability is totally unverified: they haven't actually done any testing on their product, but are pulling numbers from studies of other polyphenols, B12, and injected fisetin in rats using a different liposomal formulation.

Even at 75 mg x 60 servings, and even if we take their word for 4x bioavailability, it's still not a good deal: 60 servings at 75 mg with 4x bioavailability would be ostensibly similar to 60 servings at 300 mg powdered fisetin, or 30 servings at 600 mg, or 6 bottles of 30 x 100 mg capsules. And you can certainly do better than just suspending fisetin in water, which would close the gap on any (unproven) bioavailability advantage of their liposomal product.

Jacques Mathieu   Any way you look at it,  Fisetin is expensive because it takes a lot to make a senolytic dose and according to estimates, something like 95% is wasted by not being absorbed.   It's been suggested that taking lecithin concurrently with fisetin should increase the absorption.   Lecithin is an emulsifier which may help make fisetin more soluble.  

   As I understand it,  Fisetin does not attack cells of any kind,  it simply removes the covering or "camouflage" coating that hides senescent cells from macrophages and prevents them from being removed by normal autophagy.  Since the active time period for fisetin in the bloodstream is short and our immune systems become sluggish as we age, it seems logical to ingest a large dose of Echinacea to stimulate our immune system about a day in advance of starting a course of Fisetin + lecithin.   Reports indicate that stimulating the immune system causes it to produce more, new macrophages (or microphages in the brain) which should increase the probability of senescent cells being removed during the brief period while they're exposed.  

RAW Robert and all of you who are following this link, the following is a preliminary report on my first experience with fisetin. It was remarkable.

As background, I am a 79 year old male who has been a LEF member for the past 20  plus years after bypass surgery in 1994. I had been reading about fisetin benefits for the past year on this site and others. There was a reference to the Forever Healthy Risk Benefit aanalysis on this site and I reviewed the Risk Benefit and decided to give it a try.

 On June 6 and 7, 2020 I ingested 1.5 gram of Swanson's Fisetin ( 15, 100 mg capsules) each day on an empty stomach and did not eat for 4 hours afterword. Total cost was $10.79 for a bottle of 30, 100 mg capsules. The dosage is what Mayo Clinic  is using  in its phase 2 trials, and amounted to approximately 20mg/kg. 

The day after the second dosage, my vision in terms of color enhancement  improved significantly in that all colors became more vivid. It has remained so to this day. I realize that this is an observation and do not have any quantifiable measures, but it happened.  

I am also of the opinion that my turkey neck diminished somewhat,  but I am not positive about this observation.

However, there is no doubt that fisetin improved my strength/endurance. I have a regular exercise routine that includes chin ups and pull ups on a doorway chin up bar. I can typically do 20-21 chin ups and ~ 22 pull ups. ( As a side point my son says that I cheat.) Right after my first treatment my chin ups increased to 26 and my pull ups increased to 28.  The cheating , if any, was consistent before and after and reflects the actual fisetin effect. This increase  has remained to this day.

I repeated the doses on June 20 and June 21 and will again repeat the dose tomorrow July 4 and again on July 5. I will than go to the monthly dosage and do a chemistry profile, CBC and lipid profile in Sept. If everything looks OK  I plan to continue until Nov. when I expect to do more extensive blood work. 

Peter H. Howe   It might be prudent to remind everyone that there are 4 different types of senescent cells and each one requires a different treatment.  Fisetin treats 1 type.  Dr. Green recommends that Fisetin be taken with Dasatinib at the same time.  Some type of senergenic effect together.  Also,  Rapamycin inhibits the formation of senescent cells, but does not stop it or clear them out.  Here is Dr. Green's website which lays everything out in detail.  All backed and supported by clinical trials.  He is pathologist with many years of experience treating patients.    I personally take Fisetin and Dasatinib powder.    https://senolyticstreatment.com/

Van  Thanks Van. I am very much aware of Dr. Greens site ( have it book marked) and the fact that a large number of people have spoken well about his treatments on this site.  I do not wish to use Dasatinib as it is my "understanding" that Dr. Kirkland does not recommend it "at this time". I did not see his specific statement to that effect, however. The Forever Healthy risk assessment was also somewhat  negative in that it documented some adverse effects on patients being treated for cancer.

I personally do not agree with some of Dr. Greens other recommendations. I tried metformin several years ago, and it significantly reduced my testosterone. You can verify this side effect with a simple google.Testosterone is critical for senior men in preventing dementia, osteoporosis and sarcopenia.  I am also aware that it is probably responsible for thymus involution which is another problem, and that neutered males seem to live longer.  I am also skeptical of antibiotics as I have been trying to protect my microbiome.

I suspect that there may be more to fisetin than just its senolytic effects as many other systems were documented to benefit from fisetin in the Forever Healthy risk assessment. The effects I reported were immediate and started the day after my second dose and continue to this day. They were phenomenal which is why I decided to report it. 

Lets see what happens. 

Van you are correct. I just had a 5 hour consultation with dr green. He takes both at the same time and recommended doing a senolytic dose of each separately first to make sure you can tolerate the side effects before taking them together. He also prescribed my wife to take a zpak plus doxy, plus vitamin c for a week straight 4 times a year(so every 3 month). I wasn't prescribed this regimen because he felt she was at higher risk of cancer since she grew up next to a radioactive waste dump(he referred to it as Chernobyl but it was cold water creek in Missouri). He is a brilliant man, finished medical school at 24 and has a law degree as well. He shared some pretty cool articles with me as well. Great doctor and is in this for the benefit of human kind not just his own self interest. 

Peter H. Howe . It's true metformin can lower test. I take 100mg injected once a week of test and I'm constantly around 500 for my total test readings and that is with the metformin. The benefits are too good to pass on. If you must not take test try Berberine. Dr green thought this was just as good. 

@JOHN  Thanks  John.

 I  am hypogonadal and have always been. Use  androderm 4 mg patch, applied daily.  Metformin reduces my total t with patch from 500 to ~200. Calorie restriction does the same. I consider HRT an important part of my antiaging program.This includes DHEA and, believe it or not, making sure estradiol is in right range.

I am reluctant at this time to try dasatinib due to possible health effects. Am following those on this site who are doing what you are doing.  Will wait for Mayo to say it is OK.

If you start your program with high dose fisetin, please let us know your initial experience. Mine was fantastic in term of enhancing my color vision, strength and endurance.It was immediate and I don't think it was due to senescent cell removal.

Others have made similar positive comments about Dr. Green, and I don't mean to demean him. 

Peter H. Howe my wife and I had our two year follow up last week. Dr. Green will not prescribe metformin unless you have signs of metabolic syndrome, which I assume few of his patients have. 

Larry Thanks Larry. I had seen that position stated by others, but his web site has it towards the bottom without any caveats.

Iðunn  If your argument is that other powder forms are cheaper, then  yes, you are correct.  The cost for the liposmal for is $75. Convenient liposomal form where I don't have to mess with mixing things. I would need two bottle of Dr. Best to get to my dosage ($32)

Assuming 1 x bioavailbility = 4.5 grams. This is enough for me for the two day treament (I only weigh 100 lbs)

However - Assuming any multiple of bioavailability even just 2 = 9 grams effect that will get me through two treatments.

I think it would be very doubtful that the liposomal form doesn't increase bioavailability, that is the entire point of making an liposomal formultion (and what people are doing here with olive oil.

Personally, I prefer not to buy supplements from companies I am not familiar with or over Amazon. I trust this company (Alive by Nature) and so am willing to pay a preium for that. Also, not eager to take apart a bunch of pills and mix with olive oil.

I'm just going to experiment (today!) and see how it goes. I'm going to start with using the whole bottle over two days. Hopefully feel some difference (I'm 44 - anyone else around that age try this?) Can vary the dose a month later and compare...

Peter H. Howe I understand.  I didn't think you said anything negative about Dr. Green.  When he sees a patient he does many blood tests and takes your complete medical history to devise a plan. My wife has a different plan than I do because of some differences.  We don't take the same drugs or the same doses.

I wonder if raising your test dose would be beneficial?  Possibly 200mg injected weekly. Test does activate mtor1 so too much wouldn't be beneficial. They have done studies that show men who have higher estradiol levels do tend to live longer, and test turns into estradiol. 

I started doing senolytic doses with fisetin 12 months ago, before seeing Dr. Green. It worked great for me. I live on top of a hill with a very steep driveway. My 25 year old daughter who is a pilate instructor huffs and puffs more than I do when we walk to the top. I used to huff and puff more.  So I noticed a difference in endurance. I believe it has benefited my immune system too. I haven't been sick at all and the 2 times I started to come down with something my body fought it off. Twice where I  felt extremely tired and was running a fever of 102 degrees. This started around 2pm and I swallowed an additional 2 fisetin tablets and another zinc pill around 6pm. I went to bed at midnight still feeling very sick and with the fever. I woke up the next day with absolutely no symptoms and not sick at all. Could be a coincidence but I don't think so. Since taking Metformin and Fisetin I have noticed a big difference. Now I am on Rapa so we will see what I notice next. I can't imagine feeling any better. I would guess the feeling will just stay this way and my arthritis will probably improve. 

Simone Maher There goes my math again..

I accidentally multiplied pounds by 2.2 instead of divining to get kg. So, actually that bottle just doubled in size for me! So I only need around 900 mg per day for the two day dose.

JOHN Thank you for your kind and informative message.  I believe my My lower T levels were due to a 5:2 diet that I had been on for the past 2.5 years. The literature indicates that calorie restriction ( as well as Metformin) lowers T. I also experienced other side effects from the diet,  and I stopped the diet in mid June. I am 79 and "some" of the literature suggest that calorie restriction may not be beneficial for some seniors. I suspect that there is a negative feed back  on testosterone when AMPK is increased. 

I experienced some of the positive feedback from my first mega dose ( !.5 grams on two consecutive days) of fisetin that you also noticed. In fact I have never seen such a quick positive response from any supplement. I believe that it was due more than just its senolytic effects. 

I am concerned with possible dementia and depressed immunity as I grow older. The literature indicates that fisetin is beneficial for treatment/prevention  of both as well as as a number of other age related problems.

I will continue with my current T and fisetin treatments until mid Sept and than will do some bloodwork . Will let you know if you are interested. I do extensive bloodwork through LEF twice per year. Can't get my physicians to order what I think I need as medicare will not pay for it. I also have BC/BS and have found that Lab Corp costs with LEF are  not much different that than with insurance after co-pay.  

Take care.