#21

Good god yes, haha. Why do you even need to ask? What we really want to know is the effects on lifespan and also the healthspan/pathophysiology.

I think the dosing stuff is as clear as we can make it. The question of how it translates to humans is the question. And I guess none of us are really experts in the Marmoset model, the typical progression of OA or aging in that model. That’s where Alex’s expertise would be most insightful.

I am much younger (39) but had an episode similar to this. It turned out to be a viral infection (parvovirus). Just horrible joint pain, stiff everywhere. I only realised because my kids both got very weirdly rosy red cheeks, and some of their classmates had the same. Some ChatGPT later, and I realised that it’s parvovirus - nicknamed “apple cheek disease”, and in adult the symptoms including sudden joint pain. Took ~2 months to fully resolve.

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#22

Could be. There also may be other viruses that attack the joints.

My symptoms didn’t improve until I started back on rapamycin, whereas the Mayo online bit suggests parovirus resolves on its own – a general statement, though, and we all know individual differences vary widely. Everolimus worked on flu virus in Joan Mannick’s study, so that could be the case with parovirus and rapamycin – it may just be that nobody’s thought to try it yet.

You got parovirus when your kids brought it home from school, but otherwise it’s rare in adults, so I’m still leaning toward magnesium in my case. Whatever it was, rapamycin is taking care of it for now. Will it come back when I take my next break?

#23

I’m an N=1, but one of my primary motivations for starting Rapamycin was my osteoarthritis was becoming debilitating to the point that it was becoming difficult to continue exercise. After 6 months of Rapa my OA was materially improved, but not gone. At that point I added senolytics (100 mg D+1200 mg Q). I started the senolytics intensively at first (once every 3 weeks for 3 rounds over a couple months) then extended the time between doses progressively after that until now I’m on a maintenance program of once per quarter. The reason for the intensive treatment was two pending endurance events that would have been difficult with the OA. Again, N=1, but my OA fell off a cliff to where it’s all but gone now at age 64.

Rapamycin is a senomorphic, and D+Q is a senolytic. One of the causes/correlations of some forms of OA is a high concentration of senescent cells in the joint tissue and chronic inflammaging.

So anyway, this conclusion is incongruent with my understanding and personal experience, but again, I’m an N=1.

Hope that helps.

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#24

Thank you for sharing! Did you take D+Q once/3 weeks together with Rapa on the same day or separately? I want to try it without D, just Q.

#25

Useful input. If I’m not completely back to normal in a couple of months, I may start high-dose fisetin at about the frequency you used for D+Q.

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#26

Regarding your first question, I take the D+Q between once-per-week Rapa doses - usually exactly in the middle to give Rapa a chance to tail off through multiple half-lifes while still allowing a little time in the week for D+Q to tail off before the next Rapa dose.

With that said, there’s no science or research supporting that dosing regimen. I just made it up because it was intuitively appealing. But I’m not aware of any research saying the dosing should be separated or combined. I just decided to do it that way to minimize polypharmacy risks.

Regarding your second question, I’m not aware of any research to support your intended protocol. There is a reason D and Q are combined - their effects complement each other for the most effective treatment.

The research on Fisetin alone and Quercetin alone is mixed and not convincing. I personally wouldn’t bother. However, I found the research quite compelling when the two are combined.

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#27

I would encourage you to fully examine the published research before committing to a protocol. I’m unclear why anyone would choose a Fisetin-only protocol given the ITP results and other conflicting research.

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#28

Todd, I’m thinking about the Mayo Clinic fisetin protocol. Without looking around longer than I’d like, I can’t tell you where I copied this, but it originated from Mayo, not me:

“The Mayo Protocol consists of taking 20 mg/kg body weight of oral fisetin on two consecutive days and repeating the same dose, one month later.”

and

“New Mayo Protocol - 20 mg/kg/day (this is equivalent to around 1,800mg per day for an average 180lb person) for 3 consecutive days, resting one month, then repeating this procedure of 3 days on, one month off for 5 months total. This is a substantial increase over their previous protocol of 2 days on, one month off for only 2 months, showing Fisetin is safe and effective at even higher doses than previously known.”

I also recall reading somewhere that quercetin’s slightly more complex molecular structure could blunt the effects of fisetin’s simpler structure, when taken together. However, I have seen other opinions that quercetin would enhance fisetin.

Opinions, opinions. I do plan on using them together.

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#29

I’m trying to avoid Desatinib because it is generally not recommended for transplant recipients (I have transplanted kidney) due to its immunosuppressive and nephrotoxic potential, especially in those with reduced renal reserve. And I understand that there’s no research in using only Q instead of D+ Q. So, most likely I’ll go with Fisetin protocol b rescues it is not known to be nephrotoxic and may be better tolerated in transplant patients. Fisetin unfortunately is not well researched. The 20 mg/kg once monthly fisetin protocol is based on mouse-to-human extrapolation and has been used in pilot studies and self-experiments.

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#30

I had a similar situation with a very rapid onset right before starting rapa at the end of 2022. I thought I had broken my hand. I was told it was de Quervain tenosynovitis and is common in women over 50. During that time period I had been driving a stick shift about 100-200 miles 5-6 days per week for work. I was never X-Ray’d though and the discomfort is in my left hand as well although to a lesser degree so I’m leaning toward it possibly being osteoarthritis. It’s pretty mild and I don’t require any interventions but your situation makes me think should probably get an X-ray at this point. Thanks for sharing your experience.

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#31

My pain became milder after I stopped all supplements besides D3/K2 and reduced magnesium to once/day dose. Today is my Fisetin day - will watch what happens.

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#32

That’s fantastic news. You aren’t the first person I’ve heard report that experience. I was using a lot of supplements when my pain started and it has improved but never went away after starting rapa. I’ve gradually reduced my supplements because my diet has improved but recently started back on a multivitamin after going back to work which could be the culprit in making flare up. Thanks for the info!

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#33

I also tried Boswellia supplement for one month as @desertshores recommended and it did not help me. Maybe I didn’t take it long enough or the dose was too small. Will try again with a different brand. Topical Boswellia (frankenses essential oil) does help to eliminate pain almost immediately but the effect lasts only a few hours. I also plan to use Radiesse hand injections in hope to restore collagen. It’s a low maintenance (once every 18 months).

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#34

I went through a bottle of Boswellia (Double Wood) for my knees, but nothing.

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#35

The problem is that the Mayo Protocol on Fisetin failed. They tested it and got nil/negative results. That’s why they dropped it like a hot potato. Fisetin wasn’t worth them spending any more time, energy or money on.

“Our findings argue against what many people are already doing — using commercial products like quercetin or related compounds like fisetin that may show some senolytic properties,” says senior author Sundeep Khosla, M.D., an endocrinologist at Mayo Clinic in Rochester, Minnesota. “They’re using them as anti-aging agents without knowing if they have high enough senescent cell numbers to benefit, or what dose or dosing regimen is needed to be effective yet safe.”

It is better to prevent senescent cells from forming with a senomorphic such as Rapamycin or Taurine instead of allowing them to form and removing them later.

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#36

IMO, frankly we have very little idea of what “senescence” actually is, or how it is contributing towards ageing as a whole. There isn’t only one single senescent phenotype. Different cell types show different responses to stress, and secrete different SASP. Senescence is useful in many situations, including preventing tumour formation. So it’s a stretch to then imagine that preventing or killing them is beneficial. I’d also point out that I think reproducibility in the field is pretty low, and a lot of the models (like using H2O2 or staurosporine etc to induce senescence) are not very useful.

#37

This includes the quote you posted: https://newsnetwork.mayoclinic.org/discussion/drugs-that-kill-zombie-cells-may-benefit-some-older-women-but-not-all-mayo-clinic-study-finds/

Dr. Khosla was discussing the D+Q trial, which found the combination beneficial to bone metabolism. Although vague, he seems to be comparing the range of supplements, including fisetin and quercetin, that can be bought over the counter, with D+Q, finding D+Q to be better. That D+Q is stronger medicine than fisetin isn’t a matter of controversy.

As relaxedmeatball says, cellular senescence isn’t well understood. It is a real thing, though, and antecdotal evidence is enough for some of us to give this or that intervention a try. As is the case here.

After trying out the Mayo fisetin protocol a couple of years ago and discovering that the brand I was using, Vitablossom, didn’t contain fisetin, the recent D+Q posting encouraged me to try it again, this time with a good brand, Toniq. I just finished the first round.

Lots of articles on senolytics out there, so you’re probably referring to one that specifically finds fisetin useless. Could you provide a link to the Mayo trial you’re referencing?

#38

I was interested in Fisetin and took it based on the Mayo Clinic trials back in 2022. I was constantly waiting for the results to be published. I waited and waited. They said it would be any month now. 3 years later and still nothing. If there were any positive results, they would have published something by now. When all goes silent, it’s a sign of failure.

The only thing Fisetin did for me was give me bad diarrhea. Then I sarted Rapamycin and Taurine and never looked back.

Also, Aubrey DeGrey’s mouse study tried a pharmaceutical senolytic which actually decreased mouse life expectancy. Senolytics may not extend lifespan.

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#39

I see your point and have had the same thoughts. Dunno.

I’m going with the positive anecdotal evidence for now and proceeding. The sudden, crippling arthritis was eye-opening. There’s no doubt that restarting rapamycin took care of all but some remnants. Maybe I’m being greedy, but I want those remnants gone too.

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#40

“OA was artificially induced (ACL rupture), whereas in primates it developed naturally with aging.” This is a bigger deal, a major confound in my opinion, to equate artificially induced rupture with OA. Making it a struggle to have confidence in the conclusions. With an acute injury there is a major inflamatory response, which helps splint the joint, and in practice we would likely stop the rapamycin till the acute injury is improved, like I did for 1 yr after my knee replacement.

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