A_User
#410
I watched the video as well and he never said it made him older, especially not epigenetic age. I asked you for a quote, you didn’t want give one, okay.
Fine.
‘I made myself older by mistake.’
How do you measure that? Epigenetic age tests. I’ll even throw in a screen cap.
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A_User
#412
Title is click bait, “made myself older” is in another context “made myself unhealthier”, it makes sense to have that title so people actually click the video with regards to Bryan. It’s not totally accurate but that’s how it is with YouTube, it’s a tradeoff, but it’s still a high information title that’s directionally accurate.
First seconds in the video is a summary of the video, and that’s likely referring to the paper later in the video and not his own results, otherwise he would mention them.
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Herm
#413
“Dosis sola facit venenum” - Paracelsus. Rapamycin, when antiageing, or some surrogate measure thereof is the target effect, does seem to have an inverted U shaped dose exposure curve (IUSDEC). The benefit probably rises with increasing dose and then begins to drop off rather steeply and turning into a liability with increasing doses after a particular dose threshold is reached. I wish there were human or animal studies looking at much lower dosing regimens, say 100 - 200 mcg/day human equivalent. The problems being trying to find a well-defined target to look at, and a reasonable time frame, and of course getting the $$ to fund the work.
Nick1
#414
I recently started trending RHR with weekly Rapa dosing. I cycle off and on.
This time I am pairing Rapa dose with modest fasting for 24 hrs.
I will my panel next month including Insulin, IGF A1C, lipids.
Here are the RHR trends the day of dosing.
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I really think rapamycin works best when you pair it with the right strategies. It lowers mTORC1 activity, which seems to set things up for proper AMPK cascade activation (including SIRT1, Foxo, H2s, p53, NFkB nad much more). We can see an example of that synergy in how rapamycin plus metformin (AMPK activator) goes beyond just helping control blood sugar.
Putting it all together, my (admittedly speculative) hypothesis is that combining rapamycin, metformin, and zone 2 cardio might be the best way to boost AMPK and get the most out rapa. At the same time, rapamycin on its own can sometimes feel like a “loaded gun that never actually fires” if you aren’t also activating those metabolic pathways.
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It’s really interesting the logic that Mr. Johnson uses. He is again putting out a bunch of content in this regard. Here is one example from today.
Dr. Stanfield does a fair job discussing a recent video released by Mr. Johnson here.
I’ll go with Dr. Kaeberlein’s review on the epigenetic assessment of aging. Sadly, not ready for primetime, no evidence of what it is we are measuring.
We had as much as 25 years variance on a series of tests from different groups ourselves (my wife and I). So if you are going to serially perform these tests and they have such huge errors - how can you make any decisions based upon them? Also there is no proof that what is being measured results in health outcomes comparable to effects of aging.
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Is a ‘common sense’ answer simply not that Bryan Johnson likely has a very low mTOR activation level to begin with, due to his lifestyle and potentially other supplements?
He’s already on calorie restriction, time restricted eating, relatively low protein etc. Thus, it doesn’t surprise me that suppressing mTOR even more gave him adverse effects. He presumably also has very low chronic inflammation, relatively high opportunities for autophagy, and he claims zero cardiovascular plaque etc etc, so he wouldn’t benefit from those aspects of Rapamycin either.
As with all of these things, we would expect that the most outlying cases would be the people who benefit the most; people with high ApoB benefit most from statins, those with obesity benefit most from GLP-1RA, people with diabetes from Metformin, and people with high “growth rates” from Rapamycin.
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A_User
#419
Does anyone have the evidence and argument that CR / TRF / “Low protein” lowers mTOR?
The side effects he reported have been reported in plenty of other anecdotes.
No plaque on a CAC scan doesn’t mean there isn’t soft plaque for those reading.
Does anyone have a definitive study that shows that rapamycin lowers CRP, IL-6, or IL-11 in humans?
He said in the video he quit rapamycin 1 month before this “biological aging” paper became available as a preprint so it wasn’t relevant to his decision to quit. The reason was: decrease RHR, high cholesterol, high glucose, and soft tissue infections.
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I’m curious what you’re getting at here. Isn’t this one of the main tenets of how we think Rapamycin extends lifespan - as a fasting mimetic?
As I’m sure you know, mTOR is a nutrient sensor, responding to amino acids (particularly leucine), insulin, IGF-1, etc, and it takes part in “pro growth” pathways. I don’t think there are direct human studies, since they’d have to do biopsies of various tissues - but we can imply catabolic status from biomarkers like IGF-1, for which there’s plenty of evidence (like the CALERIE) trial.
There’s this study in mice (Calorie restriction and rapamycin distinctly mitigate aging-associated protein phosphorylation changes in mouse muscles | Communications Biology) and this one (Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle | Nature Communications) which shows similarity between calorie restriction and Rapamycin, though they aren’t identical - which is to be expected, since both are pretty “broad spectrum” interventions, especially CR. But both quite clearly show that calorie restriction lowers mTOR.
And I agree about the side effects, and I’m not saying that Rapamycin isn’t responsible. But my overall point is that I would assume somebody like BJ has less to gain from Rapamycin compared to more “normal” people.
I doubt that exists but I also don’t think it would be too valuable unless you really had a bunch of repeated measurements of different tissues over time. Those proteins all have biological functions which are quite useful, so I wouldn’t think it’s as simple as “lower is unequivocally better”
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A_User
#421
My prior is low that in the literature people know how something works and via what mechanism. So whenever I read something like this I don’t believe it at all, but it could be because it has been presented to me off hand. I see everywhere when people mention something, whether it’s a supplement or a drug or herb then I look at the literature there are multiple beneficial explanatory mechanistic effects. If someone actually virtually sat me down and went through and persuaded me this, like many have with lipids, if you understand what I mean, I might think differently.
Based on reading the summary of the two Nature papers you linked my probability that rapamycin has similar effects to CR or overlapping increased massively, so thanks for that. I’ll preliminary agree on this that it is similar to CR.
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Understood. I think the truth is that we don’t know exactly how this works. Right now, it’s a leap of faith to try and apply Rapamycin knowledge to human longevity. But what we mostly believe is that, in mammals, a constant state of “growth” shortens lifespan, which seems to be driven through mTOR. Calorie restriction pretty reliably extends lifespan of multiple species, and mTOR is again a key played in that, and we assume that it would do the same in humans. The basic idea is that during calorie restriction, processes become more efficient, we clear out old junky mis-folded proteins, we fuse mitochondria together to become more efficient, and we generally slow down the turnover of cells. However, we also need to be mindful that chronic calorie restriction probably isn’t going to be practical for humans, since we live in a world where there are pathogens, and we need to worry about preserving muscle mass and bone density etc. We do need rapid cell proliferation to fight infections, and we need sufficient calories to maintain body weight.
That’s why the idea of cyclic Rapamycin, to mimic calorie restriction, or kinda “turbo charge” those anti-growth repair processes has taken off. However, I think anybody claiming to know how this works, or anybody making super confident statements is bullshitting you.
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curt504
#424
I’m thankful for this forum and its breadth of science topics. I take growth hormone secretagog peptides: ipamorlan / tesamorlan / CJC. Which I blood tested found that my IGF-1 jumps from 159 ish to 257 ish a few hrs post AM injection. I did not cycle based on my Monday rapa dose.
There’s too many interactions for me… Maybe I should cycle HGH at the rapa troughs, over the weekend prior to my Monday rapa dose. Brain straining how ot piece this all together.
In parallel there’s similar cycling, possible over loading scenarios for the mitocondria boosing nutricals: urolithin-a, SS-31, MOTSC, SLU-PP-331, methylene blue. Per expert Alex Kikel (on youtube) depending on how functional your mitocondria are, a max dose of each should not be taken together, but cycled, and at what dose? Another guessing game for most anti agers…
Over loading this post; Kikel loves plasmologens for regeneration!!! IE prodrom.com for non food based. High quality raw egg yokes, fish eggs, high quality fatty fish. Or just take prodrom gleia. ;(
Good luck to all, curt
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Very interesting why Eric Verdin quit. According to his statements in the Peter Attia podcast, he quit, because he could feel no effects, meanwhile he had some immune suppression based on getting a pimple on the nose on the day or the day after taking a dose of rapamycin. He was ultimately taking 4-6mg once a week. He also saw no impact of any kind from rapamycin on his bloodwork. Remarkably weak reasoning as I see it. Even PA pushed back a little on that reasoning, pointing out that whatever rapamycin was doing did not necessarily have to be felt subjectively. We don’t “feel” the effects of statin therapy, but it definitely has profound impact on CV health. Not showing up in bloodwork, well we don’t know what to look for, it might be something that is not captured by standard blood tests - that’s a known limitation of taking rapamcin for life/healthspan. I may have missed it, but I don’t recall him stating how long he was taking rapa, but length of exposure may also be a factor - for me it took about seven weeks of a 6mg once a week dose to start experiencing effects on exercise capacity and recovery. YMMV.
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Where did you hear this from?
Eric Verdin revealed that in his recent interview on Peter Attia’s podcast.
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OK - so here is an AI summary of the rapamycin-related discussion from this podcast:
Rapamycin is discussed as a promising but complex intervention for aging, with effects highly dependent on dosage, frequency, and context.
Here are the key discussion points about rapamycin from the video:
1. Rapamycin as a Longevity Intervention
- Rapamycin is highlighted as one of the most promising pharmacological interventions for aging, based on animal studies—especially in mice, where it consistently extends lifespan.
- The drug is known for its role as an immunosuppressant in transplant medicine, but at lower or pulsed doses, it may have immune-enhancing and geroprotective effects.
2. Dosage and Frequency Matter
- The effects of rapamycin on the immune system and aging are highly dependent on how it is administered:
- High, continuous doses (as used in transplant patients) are immunosuppressive.
- Lower, intermittent (pulsed) doses may enhance immune function and improve vaccine response in older adults.
- A clinical trial (the Manick trial) showed that a weekly 5 mg dose improved vaccine response in older adults without the side effects seen at higher doses.
3. Human vs. Mouse Data
- While rapamycin works reliably in mouse models (even when given continuously in food), translating these results to humans is complex.
- Mice and humans differ significantly in their baseline biology and environment, so results in mice may not always predict human outcomes.
- The speakers caution against over-reliance on mouse data and emphasize the need for more primate and human studies.
4. Mechanisms and Uncertainties
- Rapamycin’s benefits may be linked to its effects on autophagy, inflammation, and possibly reducing senescent cells, but these are hard to measure directly in humans.
- The drug’s impact on glucose metabolism is also discussed, with some evidence of negative effects at higher doses.
5. Clinical Use and Caution
- The speakers express caution about using rapamycin in younger, healthy individuals due to unknown long-term effects and potential risks.
- For older adults, especially those with signs of chronic inflammation or immune decline, rapamycin might offer benefits, but more research is needed.
- Anecdotal reports suggest some people feel stronger or better on rapamycin, but these are not universal or well-studied.
6. Regulatory and Practical Barriers
- Some promising clinical trials were hampered by regulatory or bureaucratic issues, slowing progress in the field.
- There is a need for better biomarkers to measure the effects of rapamycin and other interventions on immune aging in humans.
7. Rapamycin in Context
- The speakers emphasize that physical activity remains the most robust anti-aging intervention.
- Rapamycin and similar drugs should be considered as potential add-ons, not replacements, for lifestyle interventions.
These points reflect a nuanced view: rapamycin is a leading candidate for pharmacological longevity interventions, but its use in humans requires careful consideration of dose, timing, and individual context, and should be guided by ongoing research and improved biomarkers.
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Why did Eric Verdin say he quit rapamycin?
Eric Verdin said he quit rapamycin because he did not notice any tangible benefits from taking it.
In the podcast, Eric Verdin explains that he stopped taking rapamycin for several reasons:
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Lack of Noticeable Effects: He did not observe any clear metabolic, physical, or strength improvements while on rapamycin. In contrast, he noticed measurable benefits (like improved numbers and functional strength) when using GLP-1 agonists, but with rapamycin, he “never could tell whether I was taking it or not.”
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Caution About Mouse-to-Human Translation: Verdin expresses concern about directly applying results from mouse studies to humans. He notes that while rapamycin consistently extends lifespan in mice, humans are biologically different and already have highly optimized longevity pathways.
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Potential Risks and Uncertainties: He worries about the unknowns of long-term rapamycin use, especially in healthy, younger individuals, and suggests it may be more appropriate for older adults with signs of chronic inflammation or immune decline.
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Preference for Proven Interventions: Verdin emphasizes that physical activity and exercise remain the most robust, evidence-based anti-aging interventions, and he prioritizes these over experimental pharmacological approaches like rapamycin.
In summary, Eric Verdin’s decision to quit rapamycin was based on a lack of perceived benefit, scientific caution, and a preference for lifestyle interventions with proven efficacy.
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