What I mean is an AI-generated summary like an abstract, but simpler. For example, those big data-mining type papers where the methods and conclusions are not always obvious.
However, this study is simple, basic research, and I think the AI summary posted above is longer and less substantiative than the simple study abstract.
Anyway - what do we think about Rapa and potentially worsening OA?
FWIW, the PEARL trial showed no negative signal reported for OA in women (or men), after 48 weeks. At 3mg/1-week, women have reported some positive muscoskeletal affects - in fact, it was the only measurable effect in that trial.
Two thoughts here. Obviously, dosage is an issue. Marmosets (and mice) do appear to metabolize rapamycin rather differently (and clear it far more rapidly) than humans (humans, based on the literature related to organ transplants). Therefore one should be careful translating the dosage effects from mice and marmoset models to humans. In humans, far lower dosages seemed beneficial for the muscoskeletal system in women. For men, possibly higher dosages are needed to see any effects - whereas notably in animal models here males were not negatively affected by rapamycin in the respect of OA. My thought here is that at the dosages commonly used by people for life/health extension, these findings re: OA, are not relevant to humans. This might be confirmed by the fact that there are no such OA effect reports in humans, regardless of sex in the literature, including the organ transplant literature.
Bottom line, I am not concerned that rapamycin would have a negative impact on OA in humans in dosages typically used for life/health extension. YMMV.
I’m admittedly an outlier but my ADD brain finds trouble getting through any of them, even if it’s a summary of an video, and it’s the same reason I have trouble getting through a study.
I developed a mild form of osteoarthritis on both of my hands. Started last year rather abruptly, which at first was dismissed as overusing my hands holding the wheel when on a long driving trip. Unfortunately the pain didn’t go away and recent X-ray showed mild osteoarthritis. I am not fully convinced that it’s rapamycin to blame which I’ve been taking for 15 years. It could be age and wear and tear factor, genetics, transplanted kidney which may contribute to calcium accumulation. The strange thing was that it came suddenly and changes in mobility occurred very quickly within days. I’m on a minimum rapamycin dose for kidney transplant.
Someone help me out because I’m not good at converting dosages from marmosets into humans.
Do these daily dosages in marmosets translate to human intermittent dosing? If they do, it’s a relevant data point. If they don’t, I’d throw the study away.
The 1mg/kg dosing used in marmosets is a high, but not impossible, dosing for humans. It approaches the 10mg/day dosing used in some cancer studies I’ve seen.
Here are the dose translations from the other rapamycin studies - mice metabolize rapamycin much faster. I would say we really don’t know the details of how the ITP and other trials showing the longevity impacts of rapamycin on mice lifespans translate to humans… the tests just haven’t been done (and may never, given that rapamycin is a generic medication so unless a government or nonprofit steps up to do the clinical trials, there is no financial incentive for a company to do the clinical trials).
My belief is that the best we can do is test different dosing levels and timing approaches on our own bodies, track blood test and functional results closely - and modulate in a way that we think will optimize results.
If you have not done it yet, I recommend you read the entire “Rapamycin Dosing” thread - it has a lot of good information in it and feedback from different people: What is the Rapamycin Dose / Dosage for Anti-Aging or Longevity?
I think daily dosing in mice is roughly equivalent to about once every 4 days or so in human terms given the speed that mice metabolize rapamycin is about 4 times faster.
| Sirolimus Dose |
Mouse mg/kg/day Dose |
Mouse: Blood/Sirolimus Level |
Human mg/kg/day Dose |
Dose for 60kg Human | Daily Dose adjusted for longer half-life (/4) |
|---|---|---|---|---|---|
| 4.7ppm | ∼2.24 | 3 to 4 ng/mL | 0.182 mg/kg | 10.92 mg | 2.73 mg |
| 14ppm | ~6.67 | 9-16 ng/mL | 0.542 mg/kg | 32.54 mg | 8.135 mg |
| 42ppm | ~20 | 23-80 ng/mL | 1.626 mg/kg | 97.56 mg | 24.39 mg |
| 126ppm | ~60 | 4.878 mg/kg | 292.68 mg | 73.17 mg | |
| 378ppm | ~180 | 45 to 1800 ng/mL | 14.634 mg/kg | 878.04 mg | 218 mg |
| Sirolimus Dose |
mg/kg/day Dose |
Blood/Sirolimus Level |
Male Median LS Increase | Female Median LS Increase | |
| 4.7ppm | ∼2.24 | 3 to 4 ng/mL | 3% | 16% | |
| 14ppm | ~6.67 | 9-16 ng/mL | 13% | 21% | |
| 42ppm | ~20 | 23-80 ng/mL | 23% | 26% |
Based on the FDA animal to human dosing conversion guide here.
Note: ½ life for sirolimus in mice is approx. 15 hours, vs. approx. 62 hours in humans. So, mice metabolize sirolimus approximately 4 times faster than humans.
Folks - I emailed Adam Salmon. Do people here think it would be worthwhile to do another interview at this time with Adam, to cover this paper and get an update on the Marmoset Longevity study?
Let me know questions you have, if you would like to see another interview of Adam.
He says they are almost done with the study (most marmosets have now died, I guess), but they are having delays on the pathology reports. It’s not clear when the Marmoset longevity paper will be published, but from the sounds of it at least another 6 months out.
Lara, the same sudden arthritis takeover happened to me. After a few months off, I had been back on 3 mg rapamycin with grapefruit juice every 10 days for about a month. I decided to take magnesium – it was probably 500 mg – threw the bottle away, so don’t know for sure – and full-body arthritis hit. One day I was normal and the next day I had pain all over.
What had been mild arthritis in knees and shoulders, overnight became painful in all joints – hips wrists, elbows, everything. My hands swelled and I couldn’t close my fingers. All movement hurt. Rolling over in bed or getting out of bed was an ordeal. I stopped the magnesium, gave it a few days, but nothing changed. Stopped all supplements – no rapamycin, multivitamin, fish oil, nothing.
Gave that 3 months, but still no change. Guessing that it was probably inflammation, started back with a 3 mg plus grapefruit juice dose. 3 hours later, the pain started easing. 3 days later it started coming back. Took 3 mg and grapefruit juice again. This time it was 4 days between doses, and pain was much less when it did come back. Today is the 6th day since the last dose, and remnants of the pain and swelling are still around, but nearly back to pre-magnesium days. I’m going to see if I can get back on a 3 mg plus grapefruit juice dose every 10 days, but won’t wait if the pain and swelling start to come back.
Since I was on rapamycin when it started, I’m puzzled that it didn’t prevent the problem. But there’s no question that it’s stopping it.
I’m 80 and can expect decline, but this was so sudden and dramatic that it really got my attention. Looking online, I see that others have similar problems with magnesium.
Wow! I never thought to connect it to magnesium. When the pain started I was on magnesium twice a day. I am still on the same dose of 150 mg. Do you think it could be magnesium? My pain is localized only to my thumb/wrist junction. More on the right and less on the left.
I don’t know if it was the magnesium, but that was the first time I had ever taken it. The timing and reading about the experiences of others made me think that was the cause.
The whole thing is bizarre. What I know for sure is that rapamycin is fixing it.
Definitely.
I would be interested in finding out how the arthritis phenotype was different from human age-rated arthritis.
Isnt it true that Marmoset have higher and faster back ground musculoskeletal ageing and OA to begin with as compared to humans? Rodents have more robust cartilage biology.
What clinical and radiological/imaging signals should we be looking for in humans?
So that case study mentioned OA improvement in a Rapa study, should be evaluated for the other medications and supplements involved.
I wonder if the individual from the case study was on taurine.
Do you suspect that taurine could be at play here?
Possibly. We have anecdotal reports of it causing recovery similar to what was seen in the case study. The case study mentioned the patient was taking unlisted supplements for longevity. Possible Taurine was on the list.
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.
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?
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.
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.
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.
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.