Florin I am not familiar with those studies. Would you please provide links to them? Also, most people here are following a conservative approach aligned with the Phase 2 trials being conducted by the Mayo Clinic. Those results are not yet published, so data on the effect on humans is still lacking. Also, one study indicated a toxic accumulation in the liver of mice at a high dose, which may have been a result of the DMSO delivery, but it is still unknown, so people are being conservative until more clear long term toxicity studies are conducted. Toxicity is being studied as part of one of the newer Phase 2 human trials, but we are still probably 2 years away from those results, and it is following the Mayo Clinic protocol, not the much more aggressive one you suggest.

As for myself, I have been very happy with the Mayo Clinic protocol. I have less arthritis symptoms and can see the moles and wrinkles in my skin lightening and diminishing. I have upped consumption to 2 days every 2 weeks because I was seeing a regression if I waited a full month. However, I am relatively young, so don't feel the need to be aggressive in my treatment. I also consider fisetin like weight lifting. A stimulus is good, but you need recovery time to allow the adaptation to occur. Off time is when the body regenerates and heals. Fisetin is causing a stress response and literally killing cells in the body, and that process takes its toll, so recovery is important. Senolytics cause a stress response. Your body needs to be able to adapt. Too much, and you get other negative side effects, like with the chemotherapy drugs. High doses kill the cancer, but they also begin to affect healthy cells and stress the body's ability to process and eliminate both the chemotherapeutic and the destroyed cells.

Fairy8i8 Very nice summary and thank you. Agree with what you said, and I have also gone to 2  Mayo  treatments/month ( 20mg/kg bodyweight for two consecutive days)

My own personnel experience is that there was initially an immediate response  to the Mayo protocol in that my endurance, strength and color vision were almost instantaneously enhanced. This immediate response did not increase after my first treatment, but it has not diminished either. Others on this forum have reported similar experiences.  It seems to me that there has to be more than removal of senescent cells and/or mTOR inhibition to explain the initial response.  I have done a minor literature search and have not found an explanation my initial response. I wonder if there is some sort of impact on mitochondria. It may be that my age  (80 yr old) has something to do with the initial response. 

Fairy8i8 Do you have a link to the study? Thank you

Fairy8i8 It's the same study that this entire discussion is based on. Here's the relevant info:

Ercc1−/∆;p16Ink4a-luciferase mice were fed a standard Teklad 2020 chow diet with or without supplementation with 500 ppm (500 mg/kg) of fisetin, ad libitum (approximately 60 mg/kg fisetin per day)

To determine if fisetin-mediated clearance of senescent cells impacts the health or lifespan of mice, WT f1 C57BL/6:FVB mice were fed a diet containing 500 ppm fisetin beginning at 85 wks of age, roughly equivalent to age 75 years in humans. This resulted in an extension of median as well as maximal lifespan (Fig. 5A-B).

So, 500 ppm = 60 mg/kg fisetin per day.

The WT (wild-type) mice were the only ones demonstrated to have any lifespan extension. You might think that this effect was probably all due to the elimination of senescent cells, but it might also have been caused by other factors such as chronic admin of fisetin affecting the microbiome which the paper also speculated about.

Regarding toxicity, I'm not sure what would be more toxic: acute, mega doses of (possibly contaminated) fisetin or lower chronic doses? Mega doses might be safer if heavy metal contamination would be the only concern, but what about stuff like hinokiflavon (where the dose might make the poison)? Although I'd like some human data (I did request blood test results for liver function in another thread), I'm not too concerned about fisetin accumulation in the liver; chronic administration in this study was beneficial, not harmful. The study which suggested liver toxicity used 223 mg/kg, whereas I'm referring to 60 mg/kg which apparently didn't have any toxicity. That same study also mentioned that there was no observed toxicity even at 112 mg/kg. And as for the Mayo Clinic's protocol, the reason it's going for acute admin rather than chronic is probably because it wants to avoid drug interactions (several drugs and substances were contraindicated) and perhaps hoping that acute admin would produce faster results than chronic.

Whatever happens with stress and recovery, the data we have suggests that chronic admin might be better than acute for lifespan extension. Isn't maximum efficacy what everyone wants, given the same level of safety?

Fisetin is a senotherapeutic that extends health and lifespan
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652/

Anti-cancer effects of fisetin on mammary carcinoma cells via regulation of the PI3K/Akt/mTOR pathway: In vitro and in vivo studies
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034928/

Florin Thanks for clarifying. I'm really glad you commented! I always got so caught up with the initial groups, that I failed to contemplate the significance of the final group. Refreshing to see a decrease in oxidative stress in the liver. However, we do not know how the different methods compare to longevity because the first 3 groups of mice on various diets were sacrificed rather than allowed to live. Also, there is a standard chart for adjusting dosing of animal subjects to human subjects. I don't have it off hand, but it's not 1 to 1, so 60mg/kg for humans would not be the indicated amount from this study.

Also, I will add a third day to our dose round (today) because I just took doses the last 2 days, based on the Mayo Clinic update and see how it goes. I have wondered about increasing a high dose to more days as the group of mice that was given the higher dosage for 5 days had more senescent clearance than the group given the 500ppm chow ad libidum pulsed on and off.  I never liked how that group had an initial decrease in senescent cells, but then a slow increase thereafter, even when given the chow again. It's too bad they didn't do the same imaging on the other groups to see senescent accumulation over time. If only I had money to fund research!

I had discussed which way to take fisetin with my dad. The nice thing about intermittent doses is that it is cheaper as well. As I said, I am young (40) so I have time to wait and see what becomes of the research while having benefitted on the Mayo Clinic protocol. Also, I take Biotivia Pteromax and Jarrow Broccomax daily, so I do take things that stimulate the nrf2 pathway on a daily basis already. At this point, I am more concerned with healthspan rather than lifespan.

 Michael To which study are you referring?

Fairy8i8 The only empirically-proven endpoints is that the chronic group had increased longevity and health. So, there's going to be a risk in assuming that intermittent or acute admin will provide the same or better results.

Florin Because that would cost me $6,745 a year...

Dan Nave It should cost a few hundred per year, not thousands. Remember that 60 mg/kg = 5 mg/kg HED (human equivalent dose) per day.

Florin Dr. Green has always said 3 consecutive days of Dasatinib 100 mg and 3 consecutive days of Fistein 1500 mg "every month" for elderly people.  Every 3 months for younger.  He also preaches, Vitamin C with dosing to improve bioavailability.  He leaves it up to you on whether to take Quercetin.  Says Fistein is so superior it is not necessary.

Van Interesting. Do you know how much younger "younger" might happen to be?

Moustachiarty No

Moustachiarty  At least 45, and you won't be too much off.

Mel it appears FB removed  that  Study,  do  U  remember the name of  it?

Ross Barker https://www.sciencedaily.com/releases/2020/11/201120150728.htm

aribadabar Curious enough about it to have just scheduled my first session on Thursday for the second week of December. If I decide to try three/four, will report back.

GEdwards Unfortunately you cant edit posts here.

But I assume everyone knows you could find the study yourself in about 10 seconds with google.

Michael Mel

They claim that

"HBOT were able to elongate telomeres at rates far beyond any currently available interventions"

I dont think so. I have seen reports of people have been able to achieve the same or better telomere lengthening in the same amount of time with epitalon. I dont think these researchers do much homework.

Fred Cloud ? 

https://www.amazon.com/SUPERSMART-Supersmart-Epitalon-3-mg/dp/B07LCKQJZN/ref=sr_1_2?dchild=1&keywords=Epitalon&qid=1606071759&s=hpc&sr=1-2 

Michael I have always wondered about this supplement version, it may work, it may not. I was referring to injectable. Some people have had success with oral, but not sure it will work the same. Did you see the guy on reddit who used injectable?

https://www.reddit.com/r/Nootropics/comments/4vk596/my_experience_with_epitalon/

50 year old guy took so much it lengthened his telomeres back to the length of a 10 year old kid. You arent supposed to take that much.

Fred Cloud Great! Thanks for the link

Michael Don't put too much stock on the initial reports from inferior measuring services.

See his updated data from the much more reputable and accurate LifeLength: https://www.reddit.com/r/Nootropics/comments/65rd0q/followup_to_my_experience_with_epitalon/

Good but not exceptional.

https://youtu.be/VXIqvzkTBXk

Paul Beauchemin I think I see what they did wrong, these scientists killed off too many senescent cells. There is actually a therapeutic role of SASP, the normal function of the SASP is to restore tissue function by stimulating less-damaged neighboring cells to engage in tissue repair. So if they killed off all or too many senescent cells and your skin couldnt ever enter sasp mode you wouldnt be able to repair all the missing cells you just killed off and it would form skin ulcers. So there is a healthy range of senescent cells, if you have too many it accelerates aging, if you have too few you limit repair. Its a weird catch 22. Interestingly, if you put too much rapamycin on your skin, you get skin ulcers.

These senescent cells also seem to have other effects in the body, I see the mice not only had ulcers from the skin not repairing they also had liver fibrosis. Check out this quote from a study finding.

"acute myofibroblast senescence also has a role in repairing damaged organs such as the liver and thus is likely to represent a more common mechanism to limit fibrosis"

So sasp mode may even limit fibrosis in the liver

The role of senescent cells in ageing

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214092/

Aaron Interesting symptoms. I felt like I had a sunburn the first time I took it and some random pains. I do get tired when I take it. I no longer get any pains while taking it, but some fatigue. I think it gets easier as you take it regularly. My husband, who had severe sepsis, feels like his muscles are sore like when he strength trains when he takes it, but he says that the soreness is getting less and less. I take that as a good sign that he is reducing his senescent cell load. It also does wonders for my arthritis, so the fatigue is worth it to me. I take it once a month for 3 days now. I was taking it twice a month for 2 days because I felt like there was too much regression month to month with just 2 days. Let us know how the full 5 days goes. Thanks for sharing!

Aaron When I take large doses of Fisetin I feel a weakness in thighs and I easily get sore muscle after extercise. When I have large amounts of dried Parsley (rich in apigenin) it has a sedative effect on me. Spermidine and sulforaphane also makes me sleepy. So those supplements I take only at dinner or later in the evening, (sulforaphane, Apigenin, Spermidine).

When I take Quercetin, EGCG and curcumin (BCM-95) in the morning I get a boost of energy. 

Aaron . I have yet to start taking Fisetin. 

I have some questions: is it recommended to not do vitamin IV drip while taking Fisetin or does that actually help to clear senescent cells?

Is there a combination of Fisetin with other compounds that are good for women and to maintain healthy and regular ovulation?

Are there any particular brands of Fisetin that are to stay away from?

Aaron The 4th and 5th days taking Fisetin the effects were similar, but a bit more muted. No noticeable change after completing the five days vs prior to starting. Going forward I think I'll continue to do 20mg / kg on 2x consecutive days once a month. It definitely seemed to have a bit more 'kick' than other flavonoids I've taken that have senolytic buzz.

Why such a 1600 mg and why combined with all those other things? That amount of fisetin far exceeds the Mayo protocol and as for the rest I'd worry about liver toxicity from too much of any one of them. Stacking and mega dosing them ... Is that based on any science done to date?

Whoops! Reviewing the threads here I see now why the 1600 mg. Still not certain why you'd want to stack the stuff.

Jack Black Yeah I would proceed with caution and work your way up to the 2,000mg per day dose. I have had reactions with 500mg also and so have others. I think people could really get into trouble with jumping into the deep end of the pool with 2,000mg without dipping their toe first at lower doses. I hope the mayo study results will share how some people reacted to the 2,000mg they used. Anyway, the old protocol of 500mg for 5 days should be the first stepping stone to everyone wanting to use fisetin. I was thinking one could do a hybrid protocol of using a dose escalation of say 500, 750, 1,000, 1,250, 1,500, 2,000mg once you clear the 500mg x 5 day round.

Fred Cloud I wonder if you or others might want to try the same approach. Reason being I had just 100mg of Fisetin yesterday with the big pot of black tea, green tea, cinnamon stick and sliced lemon. Even then I felt a reaction though less than the 500mg. 

The tea ingredients are intended to be synergistic but I'd be interested to know if anyone feels anything combining this with fisetin like I did. Small chance I know but maybe stumbled on a way to pep up the effect?

btw no fatty medium used this time I just took a capsule at the same time as drinking the tea.

Brian Valerie hi Brian; try your formula , on an empty stomach,  and take a 12 minute walk, also, ( maybe double the le feistin,  and you will definitely,  " feel" a difference.         Enjoy;  karl

karl kuffner Thank you very much for sharing your experience with me, Karl. I reread your post in which you related positive effects, even including euphoria! Since I'm dosing weekly, I'm able to try different protocols. There are so many different individual experiences or perceptions, here and on the fisetin thread at longecity.org., with, for example, some folks reporting better effects by taking fisetin with oil. What do you think of the notion that perhaps we shouldn't expect to "feel" anything from what could well be simply a reduction in the rate of aging?

Brian Valerie   yes, I understand.   I'm almost 71 yrs myself, however I strongly feel  ," first thing in the morning, on an empty stomach w possibly some straight black tea , quercetin a (quarter teaspoon of olive oil?), and 12 minutes brisk walk, and you should definitely have some noticeable feelings/ sensations.    On another note , my wife is much younger ," 40", and she took senolytics 3 days in a row, ( on my suggestion) and her results were STUNNING!        karl

Michael Avenoso I would definitely be taking Rapa at your age. Try adding diet and exercise to the equation if you haven't already done so as well.

This is the guy I follow the most --> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/

This is a very good article on the subject of anti aging medications.  

Michael Avenoso Yep!  Maybe we shouldn't expect to feel any improvements from what could simply be a diminishing of the rate of aging.  Before and after biomarker tests of some sort might be more telling.

Brian Valerie I don't experience any side effects, and I take the 20mg/kg for 3 days in a row every 2 weeks. I think it's better if you don't experience negative side effects. I also don't tell people about it because I am waiting for the clinical trial results on humans, but when my mom took it, she had a dime sized flat mole disappear on her face. I started tracking some moles I have developed with age (not ones I had when young), and they have lightened and decreased in size. This has been a good indicator to me, and maybe it would be more helpful to you rather than pushing and combining other things until you get a negative reaction. Also, I am not sure about the once a week protocol, as I do not know if the creators of your supplement have a scientific basis for it. If you aren't seeing an improvement, maybe try switching to a 2 consecutive days monthly treatment and see if that helps, since that is the protocol in the human research studies. Someone here said the studies were updated to 3 days, which is why I do 3 days. I do it about every 2 weeks because I start to see more wrinkles appear after 2 weeks, and when I take the fisetin, they diminish again. Oh, what a girl will do for the look of her skin!

Fairy8i8 Thanks so much for sharing your experience and wise reflections with me, Fairy.  I do agree with you that we shouldn't assume that experiencing negative side effects is an indication that the protocol is more effective.  I will certainly start looking at my moles more closely!  As far as the one day per week dosing goes, you're correct that the Mayo Clinic researchers had chosen a two days per month protocol, but of course, that is purely a fisetin study, fisetin thus far seeming to have a quite good safety profile.  The folks at the Life Extension Foundation, creators of the Senolytic Activator supplement discussed above, do have impressive academic credentials, but considering that we're barely on the frontiers of the relevant research, I'm guessing that both they and the Mayo Clinic scholars are likewise guessing!  A two days fisetin protocol was used in rodent studies, but one could argue for an even longer duration in a longer lived species like ours.   Before adding the Senolytic Activator to my fisetin dosing, I was following the two days per month protocol, again not noticing any changes at all.  THANKS to your reply, I'm going to give the two days per two weeks (then three days?) with both fisetin and the Senolytic Activator a try!

Michael Avenoso 

my understanding is serval herbs treat Lyme effectively.  But, going away from the herbs, high dose vitamin C,D, and NAD+ therapy is suppose to be magic for CLD. 
 

it’s NEVER too late to get better. Just don’t think it will always be this way. 

Michael Avenoso There have been alot of advancements in chronic lyme. From biofilm busters, persister cell treatments like disulfarim, pulsing antibiotics, abx combos for persister cells. I would try all of those if you havent already. Find a good lyme doc or just treat yourself.

Michael Avenoso in the event you need an internist with Lyme specialty, if you are in the Charlottesville area I can give you a contact.

Thanks everyone. I've been dealing with chronic Lyme since 1991. Tried all the above including Disulfiram and NAD infusions. Mild HBO therapy has gotten me somewhat functional again.

Michael Avenoso You tried all those approaches and failed? Well if all else has failed then you should read this book.

Lyme Disease Supercharge: The Revolutionary Approach to Getting Better When All Else Fails

Fred Cloud Thanks Fred. I explored mold illness with Ritchie Shoemaker. M.D. Unfortunately it didn't help. At this point I am simply trying to stay alive long enough for an effective therapy to be discovered.

Michael Avenoso Hi, Michael -- I did not check all your postings, but noticed mention of Lyme,  so thought I'd mention a site I've been familiar with for number of years:

https://www.betterhealthguy.com/

In addition to having had Lyme, he has had other issues, but has much info, etc, how he has flourished.

Michael_B Thanks Michael, I am familiar with him. He's an excellent resourse.

Michael Avenoso Based on just some of your postings, I assume you were familiar with BetterHealthGuy.  Have you solved your Lyme issue?  I understand especially for allopathic community it is mostly a puzzle, but I think many holistics have treated it successfully.  Ozone IV's?  Regards,

Michael_B I haven't done IVs with O3 but I do have a medical grade ozonator and and have used it extensively. My best results came from using a mild hyperbaric chamber daily for a long time. Paired with a Ketogenic diet I went from a wheelchair to hiking the local trails.

Michael Avenoso By medical grade, I assume you mean with oxygen tank, and ability to adjust flows. Ozone rectal insufflation is about 80-90% as effective as o3 IVs, per Frank Shallenberger, MD, whom taught many of the practitioners. 

Do you also have a steam cabinet, where ozone can flow in?  That would immerse entire body in o3, after the heat / sweat, opens the pores. For general health I use 100 degrees, 20 minutes, at about 20 - 25 gamma.  For you --and others -- one might find a colonic practice / chiro / spa,  where one could try a few sessions, prob at about $75 - $125 per session.

Keto (esp organic) likely best for all illness.  I tried the portable, inflatable hyperbaric at my holistic MD prob 20+ years ago, but was too claustrophobic.  Besides the larger units (some one can sit/stand) have greater capabilities, but I have not even tried that - yet.  It appears you have investigated the better holistic options re Lyme.  Maybe senolytics, Rapa, etc, may provide additional synergies. Best wishes,

Michael_B Wow, we have been down some of the same paths! Yes O2 tank and flexible settings. I did rectal insufflations for months with no benefit related to Lyme Sx. I use a sauna but only tried the O2 steam cabinet a few times but I just didn't like the experience.

I agree on the Keto diet as a medical intervention. I did it for 2 years along with the mild HBO with amazing results. I am currently low carb but not Keto. Many people confuse the two.

I have experimented with Dasatinib/Quercetin and Rapamycin. Currently taking Life Extension's "Senolytic Activator" and planning on restarting Rapamycin. 

Be well!

Michael Avenoso I knew there was at least one nut, similar to myself.  Re diet, I'm organic Paleo, which is basically keto, but some vegs, even some carbs.

I started Rapa about a month ago, but going slowly, Sat morning I took 3 mg;  will build to 5-6 over next few weeks.  I still do F + Q, never tried D.

Ozone has been effective re Lyme.  I've gong over the years number of times to David Minkoff, MD, FL, whom has a large practice with Lyme patients flying in.  Shallenberger says O3 insufflation is about 90% as good as o3 IV, so surprised you have not recd benefits.

Kelly K Just be careful how regularly you take Q. When it was given to mice every day it reduced their lifespan by a lot. It has a toxicity and the benefit seems to derive from occasional harnessing of that toxicity. Personally I'm only considering Quercetin for D+Q type hit and run therapies. Fisetin daily on the other has some genuine advantages I've seen myself, some mentioned by folks in the thread above, but anything regular 100mg sounds fine. As detailed above even just 500mg Fisetin had some sort of accompanied immune reaction. 

Jack Black 

Van Dr Green as dropped Q from the protocol.  It is now Fistein 2,000 mg + Dasatinib 100 mg. x 2 days once a month or once every 2 weeks.  Not for your reasons, but Fistein works so much better.  Young people 2 days every 3 months

Van So it's now F+D ? Wow hadn't heard that. Interesting.

Van What's his definition of young? I'm 50 and certainly my doctors describe that as young. :)  

Jack Black https://senolyticstreatment.com/

Kelly K To explain my comments above the reason I suggest not using Q at all regularly is the reasoning that it is chronic non-fatal toxicities that promote cancer. This idea is explained very well here; https://www.youtube.com/watch?v=nrqXKf3tprE

Then consider this review here; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ where Q was actually detrimental to mouse lifespan. If that is the case why would chronic administration benefit humans?

Aside from hit and run senolytics (alongside other compounds, Q doesn't seem to work alone) I am not aware of anything beneficial around Q, especially chronic dosing. Other forums has people talking about kidney damage. If you can direct me to anything to the contrary I would be happy to read it.

Fisetin seems a bit better. Still wouldn't take it daily but I can attest to there being benefits to the stuff certainly short term.

I will also hold my hands up and state that I've bought some of the Q based once a week senolytic pills from LE. Bit of an experiment, but currently on hold as my covid jab is next week and I want my body to be in a 'normal' state for that. But mainly I'm sold on fisetin. Even my 500mg single dose seems to have aided the color perception in one of my eyes, which another poster here had noticed with a higher dose.

Jack Black Yes Jack I totally agree that we should not use any anti-oxidants when we are clearing out senolytic cells. Just in case it may also clear out the nutrients responsible for clearing out aged cells. I may take them in the evening but not during the day. There is too many unknown here. What we do know is that it seems to work for people and when they do the studies they make everyone stop taking  all other  nutrients so that the other nutrients do not interfere with the senolytics. So we should try to mimic as much as possible what they do in the studies. Cause we know that protocol works. So it is pretty obvious to me that we should avoid whenever possible avoid  things which may disrupt the effectiveness of D and F and maybe Q...

garland Jack Black

Yes some senolytic substances and substances that drive apoptosis works (at least partially) through ROS dependent mechanisms and powerful antioxidants like acetyl cysteine can reverse the ROS accumulation.

I also consider the fact that ROS can create an environment which can make cell death and Autophagy go wild and cause (for instance neurological) disorders.

Just as well as antioxidants can impair ROS driven senolytic processes, we need antioxidant mechanism to protect the brain.

This leaves us with the quest to balance the extraordinarily complex cell physiology that is distorted by processes that drive ageing. We might need ROS for some positive cellular adaptations as well as ROS can be detrimental in other cellular settings.  

Btw, Kirkland speculated in one paper that senolytic treatment might be improved if its combined with fasting or exercise. 

https://www.hindawi.com/journals/omcl/2014/906804/

“Piperlongumine (PL), a natural alkaloid from Piper longum L., possesses the highly selective and effective anticancer property. However, the effect of PL on ovarian cancer cells is still unknown. In this study, we firstly demonstrate that PL selectively inhibited cell growth of human ovarian cancer cells. Furthermore, PL notably induced cell apoptosis, G2/M phase arrest, and accumulation of the intracellular reactive oxidative species (ROS) in a dose- and time-dependent manner. Pretreatment with antioxidant N-acety-L-cysteine could totally reverse the PL-induced ROS accumulation and cell apoptosis. In addition, low dose of PL/cisplatin or paclitaxel combination therapies had a synergistic antigrowth effect on human ovarian cancer cells. Collectively, our study provides new therapeutic potential of PL on human ovarian cancer.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253430/

“Piperlongumine selectively kills cancer cells and increases cisplatin antitumor activity in head and neck cancer.Piperlongumine killed HNC cells regardless of p53 mutational status but spared normal cells. It increased ROS accumulation in HNC cells, an effect that can be blocked by the antioxidant N-acetyl-L-cysteine. Piperlongumine induced selective cell death in HNC cells by targeting the stress response to ROS, leading to the induction of death pathways involving JNK and PARP.”

https://www.urotoday.com/recent-abstracts/urologic-oncology/investigative-urology/52516-piperlongumine-induces-rapid-depletion-of-the-androgen-receptor-in-human-prostate-cancer-cells-abstract.html

“BACKGROUND:Androgen receptor (AR) signaling is regarded as the driving force in prostate carcinogenesis, and its modulation represents a logical target for prostate cancer (PC) prevention and treatment.

RESULTS:The results of our experiments demonstrate that PL rapidly reduces AR protein levels in PC cells via proteasome-mediated ROS-dependent mechanism.

CONCLUSIONS: Our investigation demonstrates for the first time that PL induces rapid depletion of the AR in PC cells. As such, PL may afford novel opportunities for both prevention and treatment of prostatic malignancy."

The Interrelation between Reactive Oxygen Species and Autophagy in Neurological Disorders (hindawi.com)

“High oxygen demand is always accompanied by more ROS. The brain is rich in various polyunsaturated fatty acids sensitive to ROS, but is relatively devoid of antioxidant enzymes and GSH, adding that neurons are considered terminally differentiated cells, which make brain tissue more inclined to suffer damage from ROS . Robust evidence suggests that ROS display a recognized role in neuronal death after brain ischemia.”

Staffan Olsson Yes I do intermittent  fasting when I do this. I do believe it helps enhance the process. I do feel a bit drained after about 3 days. But it should be noted that the owner of Life Extension recommended that one NOT do ANY EXERCISE DURING THIS PROCESS!!! Not sure why as it was never explained that I could find.  I still walk but not too extreme.... 

Sebastian Fisetin was found to reduce senescent cells in fat tissue as well. There is really only 1 study on Fisetin as a senolytic. They looked at several possible polyphenols, and fisetin was so much more efeective than even quercetin (alone) that they focused the study on it. You can google the study - Fisetin is a senotherapeutic that extends health and lifespan by Matthew J. Yousefzadeh, Yi Zhu, [...], and Laura J. Niedernhofer.  

They went into Phase 2 clinical trials after this study, and are currently researching it on humans. You can find those studies by going to clinicaltrials.org and searching fisetin. The first, and a couple since, have set dosage to 20mg/kg body weight for 2-3 days in a row per a month. The fisetin is in a capsule with peg400 and a couple other things to increase absorption, as it is not water soluble. That specific capsule is not commercially available, so some here take Bioperine to increase absorption. I have taken a CoQ10 supplement with bioperine, and it upset my stomach, so I just take my fisetin with a meal with fat or with some omega 3 fish oil liquid that I often take. I just take the capsules as they are where some here will directly mix the fisetin powder with olive oil or some other oil. I would just try it, and remember that the best therapeutics have few side effects, so hopefully you won't feel much. I get a little extra tired. My husband says he feels sore muscles like after lifting weights, but he also had severe sepsis, so he has a lot of cellular inflammation from which to recover. He feels less sore now than when first taking it after the sepsis. My uncle said that just the fisetin according to the 20mg/kg for 2 days a month helped his arthritis significantly so his fingers hurt much less. Good luck! I am 41, I have taken fisetin for about 3 years or so. I mostly notice some reduction of fine lines in my skin and the cover of a fee moles. However, as my friends are aging, they are beginning to notice that I am aging slower than they are, so I think it may be doing something. The next 10 years from 40 to 50 is really the time to notice as aging speeds up. My runner friends all look young as well, so don't forget some good exercise to keep you healthy and promote autophagy.

JGC Thank you for your fast reply and all the effort you are making

Fairy8i8 I really appreciate this detailed description!! Thank you very much.Only 1 question left : Does it make sense to take F and Q ? Together or alterning or maybe just concentrate solely on F ? Sebastian 

JGC I agree. Because clinical studies haven't been done with the 2 together, it would just be self experimentation. The nice thing about these plant compounds is that they are well studied in other applications and don't seem to have serious negative effects, even at high doses.

JGC and Sebastian, If you would want to take 1gm of Fisetin and 1 gm of Quercetin, I suspect you could leave off the Quercetin if you increase the Fisetin to 2gm.  The reason I say this is that I feel that, at the least, Quercetin might be considered to be sacrificial and extend the effect of Fisetin.  Both F and Q inhibit CYP3A4 activity in a dose dependent manner.  If you have plenty of Fisetin and are not concerned with the cost perhaps you could just bump up the quantity of Fisetin that you are using.  I would also recommend mixing with olive oil and either adding a goodly amount of ground black pepper or some piperene.  I have not seen any information that indicates whether you should take the piperene an hour before, or if you should just take it with the rest of the dose at the same time.  I do it at the same time.   The tests with Dasatinib that I have seen have all been done with Quercetin.

I just did another protocol this week as follows.  I wanted to do both the Dasatinib + Q and the Fisetin + Q instead of doing two separate protocols.  What I ended up doing was taking 100mg of Dasatinib with 500mg of Quercetin in the morning, either before or after I had eaten.  In the evening, on an empty stomach, I took 1500mg of Fisetin and 1000mg of Quercetin all mixed in olive oil with a couple of 10mg pills of bioperine (piperene).  I did this for 3 days in a row.  (I am 69 and about 175kg)

The reason I separated them like this is that I did not want to potentiate the effect of the Dasatinib as I am somewhat leery of getting too high a dose of that, but I wanted to potentiate the Fisetin/Quercetin so that it was absorbed better. 

With this protocol the only real side effects were some headache from the Dasatinib, and some slightly loose stools on the fourth day rather than the all day diarrhea that I had experienced earlier after 2 doses of Dasatinib at 200mg with bioperine...

Dan Nave According to the rep at Sabinsa, Bioperine should be taken at the same time as the Quercetin, the reason being that the piperine will only be active for about 15 minutes after ingested.

chuck stanley In my mind this is the best site for senence treatment https://senolyticstreatment.com/

Van Yes, absolutely the best site, with the most relevant studies! And if its been a while, its well worth the re-read!

@JGC did you see chuck stanley's comment about the timing of Bioperine ingestion?

JGC Very interesting. I will ask the manufacturer to explain the contradiction. I think that a significant portion of Bioperine sales are for use in compounding with bioflavonoids, so the efficacy of simultaneous ingestion is crucial.  

JGC Correct me if I am wrong, but isn't the enzyme in question, and the action we are looking for, in the intestine?  How are we testing this if it is given intravenously?

JGC and Dan Nave This clarifies the mechanism: "The mechanism of action  responsible for the bioavailability enhancing effect of Bioperine® is because a small amount of piperine stimulates the release of catecholamines, thermogenic hormones whose activity is made possible by the presence of cyclic adenosine monophosphate (cAMP) . The thermogenic effect has been localized in the epithelial cells of the intestine that increase the absorption of nutrients. However, the catecholamine-mediated thermogenic response is relatively short. Therefore, the window of absorption has a narrow temporal scope. These thermogenic properties may explain how a minimal amount of BioPerine® can produce such a powerful effect on the uptake of serum nutrients"

JGC Piperine acts as a bioenhancer both in the Gastrointestinal tract and in the liver and in othter metabolic processes responsible for the elimination of substances:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634921/

From: Bioavailability enhancers of herbal origin: An overview:

" 6.1. Mechanism of action of piperine
Different mechanisms for the bioenhancer activity of piperine have been proposed including DNA receptor binding, modulation of cell signal transduction and inhibition of drug efflux pump[29].

In general, it inhibits drug metabolizing enzymes, stimulates absorption by stimulating gut amino acid transporters, inhibits the cell pump responsible for drug elimination from cells and inhibits intestinal production of glucuronic acid.

It may increase the absorption of drug in the GIT, or inhibit enzymes responsible for drug metabolism, especially in the liver when the drug passes through the liver after absorption from GIT. Oral administration of piperine in rats strongly inhibited the hepatic arylhydrocarbon hydroxylase and UDP-glucuronyltransferase activities[30].

Another study demonstrates that piperine modifies the rate of glucuronidation by lowering the endogenous UDP-glucuronic acid content and also by inhibiting the transferase activity[31].

Piperine inhibits human P-glycoprotein and cytochrome P450 3A4 (CYP3A4)[32]. Both the proteins contribute to a major extent to first-pass elimination of many drugs.

Some of the metabolizing enzymes inhibited or induced by piperine include CYP1A1, CYP1B1, CYP1B2, CYP2E1, CYP3A4 etc. Most of the drugs metabolized by these enzymes will therefore be influenced by bioenhancers.

Some other suggested mechanisms include making target receptors more responsive to drugs, acting as receptors for drug molecules, increasing GIT vasculature by vasodilation to increase absorption of drugs, modulation of the cell membrane dynamics to increase transport of drugs across cell membranes[33].

JGC  What you write should be about optimal, at least according to what the research  can tell us now. 

There is an obvious advantage of using piperine, this since it makes it possible to use exact doses every time. But when it comes to apoptosis and cell cycle arrest, black pepper has other advantages. In theory the other effects could be beneficial in a senolytic treatment.  

https://www.mdpi.com/2072-6651/12/12/747/htm

"Overview of the Anticancer Potential of the “King of Spices” Piper nigrum and Its Main Constituent Piperine"

I just wanted to post this again separately as I think it is a good compromise for incorporating a protocol of dasatinib, quercetin, fisetin and bioperine.

I just did another protocol this week as follows.  I wanted to do both the Dasatinib + Q and the Fisetin + Q instead of doing two separate protocols.  What I ended up doing was taking 100mg of Dasatinib with 500mg of Quercetin in the morning, either before or after I had eaten.  In the evening, on an empty stomach, I took 1500mg of Fisetin and 1000mg of Quercetin all mixed in olive oil with a couple of 10mg pills of bioperine (piperene).  I did this for 3 days in a row.  (I am 69 and about 175kg)

The reason I separated them like this is that I did not want to potentiate the effect of the Dasatinib as I am somewhat leery of getting too high a dose of that, but I wanted to potentiate the Fisetin/Quercetin so that it was absorbed better. 

With this protocol the only real side effects were some headache from the Dasatinib, and some slightly loose stools on the fourth day rather than the all day diarrhea that I had experienced earlier after 2 doses of Dasatinib at 200mg and Quercetin at 1gm with bioperine...

Dan Nave hello, after some research I've found that bioperine potentiates flavanols.... Like fisetin and Q. The primary way to potentiate Dasatinibis taking it with grape fruit juice (white works best, not pink). But separately the dosing is not generally needed unless you continue to take the large dose of Dasatinib instead of half in the am and the other in the pm.  You might try just splitting it all am and pm.  The GF juice does not potentiate Q or Fisetin but it certainly does for the D!  Be careful with other meds you take as the GF juice effect lasts about 12 hours but only affects certain meds.  If you have other meds search their names with ' and Grapefruit juice' .

JGC Isn't the action of Bioperine in the intestines, rather than in the blood?

Jay Orman Addition to my note about BPH: The article mentioned did not have any reference to senolytic activity which I found interesting.  

Jay Orman There are many ways to improve prostate health with natural substances.

To name a few: Grape seed extracts, quercetin in combination with green tea and gamma tocotrienol. Broccoli extracts+curcumin+green tea+pomegranate. And yes Fisetin is one. 

After all a long life come with an increased risk of prostate related issues that might need to be managed. So the forum might use a special section for sharing information about this area.

Sebastian I like to take it on an empty stomach, but I add 1 Tablespoon of oil and mix the fisetin into it.  I don't have data to say taking it on an empty stomach is better, but I suspect it gets absorbed faster and more completely that it would mixed with a stomach full of food.  Fisetin is oil soluble but not very water soluble so that is why I add the oil.  I also add some bioperine or 1/2 tsp of ground black pepper.  (Yeah, it tastes terrible...)  It seems to have worked well for me.  I would suggest not taking any other supplements those days so they don't interfere with the action of the fisetin.  Maybe even stop supplements the day before and the day after.

You might want to take 1 capsule only at first to make sure you don't have any sensitivities to fisetin or bioperine.

Allen I'm glad they don't add it.  If they added 10mg of Bioperine to each 100mg capsule of fisetin you would be getting way to much since you would use 10 or more capsules at a time.  Better to add the amount you want separately.

JGC I am considering the possibility that using 1/2 tsp of freshly ground black pepper may be superior to using Bioperine.  Previous discussion indicated that the effect bioperine may last for 15 minutes.  Perhaps, like most refined products the bioperine is assimilated quickly and used up quickly.  The ground black pepper I would expect to take more time to be absorbed and may therefore act over a longer period of time allowing more fisetin, etc, to be absorbed.  I did notice a much stronger reaction when I took doses of F, Q, and C, when I took the 1/2 teaspoon of black pepper than when I took it with several pills of bioperine.  Of course, this is just preliminary conjecture on my part, but I think the next time I will try the black pepper with my F + Q...

Dan Nave I haven't been able to find any study that shows the amount of increased absorption of fisetin that is provided by piperine or Bioperine. I spoke to a scientist at Sabinsa and he guessed that based on fisetin's structure,  the effect of Bioperine would be similar to to the effect on pterostilbene, about a 2.27 fold increase. But the effect is dose-dependent. So I scaled up from the mouse study that used piperine  with resveratrol to get an enhancement of 229%. I calculated that for me at about 66 kg, I will expect an effective dose of 2000 mg fisetin if I coingest 1000 mg fisetin with 5mg Bioperine. Actually, I take 500mg each of F&Q on day 1. I do take the dasatinib separately, early in the day and the flavonoids about 5 hours later. On day 2 of my D&Q&F cocktail I take an additional effective dose of 1000mg of just fisetin. that seemed reasonable and I havent had any side effects. 

GEdwards GEdwards ARE YOU saying that pink grapefruit juice does not work vs white.

Van I use white grapefruit juice to enhance rapamycin bioavailability. Something I read, years ago, from a nutritional guru, is that the compound that inhibits the breakdown of relevant pharmaceuticals is much more concentrated in the skin of the grapefruit. When I've only had access to red gf (not juice) I include eating some of the skin, for possible enhanced benefit. Haven't looked into it lately, though.

GEdwards The last line of the article reads, "Thus, colored grapefruit juice may produce drug interactions at the same rate as white grapefruit juice." May or may not is the operative word here.

BobM 

Fisetin and cancer fighting.

found it: 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261287/

This is an excellent read.