@ng0rge I loved doing the research on this, as I was challenged by multiple colleagues on why I was supplementing people for no reason, and then in my chat with Matt K I expressed some reservation around why he would have this as a strong recommendation. Incidentally, I think he is right on this one … I just don’t think we have the clear evidence yet – but if someone would do the right study, I think the evidence will be there. Thanks for reading the blog … it is really long, but I think putting things in context is really important on this topic.
@John_Hemming This is a fascinating issue of whether we do harm to blunt seasonal variation by supplementing. This is where I think the best situation is to try for 3 months to do what you can behaviorally, and then supplement if needed. In this situation, you simply move the curve upward on your level, above a minimal harmful threshold, but should continue to have highs in summer and lows in winter.
@AnUser - I think all cause mortality is a really important outcome. However we have 60,000 IU monthly given, and just don’t know what their levels were. They weren’t selected or monitored based upon deficiency. We know people with high vitamin D levels have worse outcomes - again, it is a serious methodologic error to just blindly supplement when it is so easy to test levels and target to a certain level.
@KarlT - really interesting, I agree, many things that used to cycle, we’ve eliminated by our hardship and environmental changes.
@Dr.Bart Clinicians rule and researchers drool … well they are pretty smart, it’s just a different animal and perspective
@PBJ I think the experience that doctors are narcissistic is unfortunate. I’ll apologize for doctors if that is what you’ve experienced. I’m not, and learn a stack from my well educated patients (less from my patients in the ER).
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@DrFraser It seems you’ve also mastered a happy/optimistic personality (at least in your writing 
) That should add an extra 5-10 years of healthy lifespan. 
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I have contacted them and created a google sheet which I sent to them and tried to group the questions in a good way because this will be multiple episodes with all the questions we have. I have also added your question to the sheet now.
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So you judge people by their ability to produce a “video” 
Send me a link when you finish a medical school, residency, fellowship, all the licensing exams and spend 25 year providing medical care.
Feel free to put me or any other “narcissistic” providers on the ignore list. Clearly we don’t meet your “standards” for expertise, so why bother being exposed to our opinions?
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PBJ
#146
Thanks for proving my point.
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Other people you’d like to hear from?
See list of presenters here:
https://www.americanagingassociation.org/2024-age-speakers
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I’d love for Dr Kaeberlein to dig into the benefits and hazards of blood / platelet / plasma donation for diluting old blood factors, dumping iron, losing Klotho, etc. Is it too late to ask?
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Irina conboy is at the meeting mentioned above…
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Here is one AMA episode that they have created thanks to this thread.
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Thanks! This was a great Matt Kaeberlein interview – confirming what we know about rapamycin - a few possible maybes, but as always Matt is not one to over speculate - is comfortable saying no research on things yet - or we just don’t know.
Which is why he remains one of the few researchers on rapamycin that I (and others) trust and respect.
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I agree, @Agetron. We are all acting on our own hypotheses that go well beyond what the available evidence can reliably inform. It is nice to hear him confirm that.
Thank you, @Krister_Kauppi for trying to get all of us satisfaction on our questions!
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@Krister_Kauppi Nice work! I’m impressed with how you have made a mark in the longevity space through intelligent effort and persistence. Well done! And thanks.
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@Krister_Kauppi Yes. Thank you Krister for compiling the questions!
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Notes from video —- several surprises
- don’t worry about diet or cardio exercise around Rapa dosing
- no rationale for limiting protein around Rapa dosing
- muscle gain might be better without Rapa. Take Rapa holiday to gain muscle, then hold onto muscle while dosing Rapa. And better to avoid resistance exercise the day before and day after Rapa dosing
- no data exists on mTOR rebound. Fasting followed by overeating may have negative consequences
- doubling dose (12mg vs 6mg) while doubling dosing cycle (2 weeks vs 1 week) will result in higher peak of rapa and longer period of time with no detectable levels of rapa vs weekly. Is one better? Higher peak probably better delivery to organs that are hard to reach (brain?). A guess.
- Matt started doubling his dose/period (16mg every 2 weeks)
- does tolerance to rapa develop? No data. But a guess is it’s possible but daily dosing in mice still works.
- what is a good trough rapa level? Undetectable for at least a few days a week before next dose. Low blood rapa doesn’t insure no mTOR inhibition in organs
- no evidence of bone loss in humans from rapa. Rapa promotes regrowth of oral bone. A ton of rapa might hurt bone.
- becoming convinced that 1x/wk Rapa preserves muscle
- sglt2 inhibitors vs mTOR inhibitors? Sglt2 benefits probably best for people with metabolic issues while rapa seems to address aging in general (my interpretation? Maybe better side effects for rapa but no proof
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Actually, Matt got this wrong. There is data on humans regarding mTOR rebound. Based on the study provided by McAlister, at 20 mg or less, there is no rebound. At 40 mg, there’s a 50/50 chance. Most people don’t dose over 20 mg, so it’s not an issue for most, but somewhere between 20-40 mg, rebound in humans becomes an issue. So, I’m staying at 21 mg. I’m living on the wild side.
I’m more worried about mTOR2 inhibition. @Krister_Kauppi maybe you can ask MK about this? How big of an issue is this and at what levels do we need to worry about it?
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@Krister_Kauppi thanks for your efforts on getting the questions to Matt. You’re really helping move things forward.
You may want to include (and we may want include when we post a question) a link to the research that we are asking about - so Matt and his Optispan people can review the research beforehand. For example, the full thread on MTOR rebound would ideally be something that I think Matt would be interested in reviewing prior to answering: Rapamycin / MTOR Rebound effect in 3/12 non-GF and non-Keto patients
In many cases we’ve discussed and dissected these types of issue more than Matt likely has - so it would be good to bring him up to speed on the research and discussion.
Did anyone else notice the Easter Island Moai sculpture in the background of the podcast
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Nice summary. I heard a few points slightly differently than you did.
He said there might be a case for avoiding resistance training the day of the dose and the day after. He did not mention the day before the dose. (He also mentioned this was speculative since it is not currently known if there is an impact.)
He said he has been taking 8mg per week since January.
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One other point I found very interesting was the comment on how quickly your blood sirolimus levels might be going down to under 1ng/ml. It was interesting that Matt tested at day 3, 4, 5… and found that it was already below 1 ng/ml after day 3. I had not considered testing earlier than day 6 or 7, but now I will test earlier. This might be a reasonable indicator that you’re “safe” to try higher doses if you’re not getting significant side effects, and you’re dropping to under 1 ng/ml after a few days and you’re at that level for a few days prior to your next dose.
So - I’ll use that new service from Healthspan $25 Rapamycin blood tests
and test at day 3, 4, 5, etc. when I’m on a weekly dosing schedule, and perhaps try testing at days 7, 8, 9, 10… if dosing on a once every two week schedule.
If other people try this, please post your results.
I also am interested in doing this with Everolimus. I will also try the blood sirolimus level test after dosing Everolimus, as I wonder how specific the test is and if it can differentiate between sirolimus and everolimus.
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Just did here Blood concentration of rapamycin (N of 1 dosage, model and biomarkers)
BTW the optimal protocol to fit the rapamycin pharmacokinetics is 2h for peak then 24, 48 and 96h
As you can see in my results that’s enough to get a very good fit.
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Do you have a spreadsheet you can share for others to create similar graphs from their experiences and tests?
How did you create the graphs? (what app)?
