Yes, but (a) in all three paradigms (as well as @mkaeberlein’s late-life megadose study) the animals were dosed daily for an extended period of time, not taking low doses once a week (see above re: trough levels in serum), and (b) there’s a problem with this study, as I pointed out before (and see followup answers to questions by @约瑟夫_拉维尔)…
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The researchers in SPF vivaria take extreme precautions to maintain the SPF status, including wearing space suits and regularly testing the animals and quarantining infectees. See here for a monkey being fed for a CR study. Their food is typically autoclaved and thy are given reverse osmosis water.
You will recall that a couple of years ago, people couldn’t even be convinced to keep their masks over their noses in the grocery store …
You’re right that we conversely have the advantage of vaccination and Abx. Still, people die and are disfigured by infections all the time — and @mkaeberlein got a significant bacterial infection during a recent rapa cycle.
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@约瑟夫_拉维尔 and @DrFraser
I just want to make sure I’m getting you guys straight here.
@约瑟夫_拉维尔 - You’re dosing 4mg every 14 days with grapefruit juice (GFJ) and no food, which results in an effective dose of approximately 12mg. I’m confirming this because I saw a different post of yours and got confused while reading your posts in this thread.
@DrFraser - For your neurodegenerative plan with one of your patients, are you administering a larger dose of 12mg with GFJ to achieve a higher effective dose, or are you using GFJ to increase a smaller actual dose of around 4mg to an effective dose of 12mg, similar to what @约瑟夫_拉维尔 is doing?
I’m monitoring levels so we see where we are at. I’m getting more experience with what to expect, but there are variances. I’m going to order a whole lot of these for myself and wife and get some data collection that will augment what I see from my patients. I’m not convinced of the size of effect with GFJ - but will do a little testing over the next couple of months and feedback my own data. Naturally I cannot do this with my patient’s data, except in generalities - but I’d like to put up a bit of meaningful data on N=2 both with and without GFJ.
For neurodegenerative patients, I am goaling a 20 hr level of ~6.5 ng/mL as this usually maps out nicely for a 14 day interval. For folks wanting a 7 day interval and less concerned about pushing up to a higher serum level then a 20 hr level of ~4-4.5 ng/mL usually works out. But we do need to get a repeat at 48 hours after that initial if we are going to map out half life - and the individual needs to take it the same way each time.
Usually I go with 1 oz of nuts and then if doing GFJ - some will do it initially, some will to initial and next day, others daily for a few doses. As long as we measure levels, any of these can work.
It is interesting that @约瑟夫_拉维尔 and @John_Hemming are taking on protocols that pretty much do exactly the same thing - or would be predicted to if levels were done.
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I haven’t found a route towards Rapamycin blood testing in the UK. I would quite like a broad test of the pharmacology of a number of things I am doing, but I have to stick to my weekly blood panels.
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You made a very good point here! If you listen to the new Adam Salmon podcast you’ll see he says that actually, the human environments are probably a lot more like the marmoset environments than “wild” environments.
So… perhaps we are a lot more close to translatability of this research than one might assume. This bears deeper research. I suspect the actual risk of our personal environments varies a great deal. If you work in a hospital that is one (probably higher) risk environment, if you work alone at home doing telecommuting its a very different risk profile.
We might need to develop our personal rapamycin dosing protocol with considerations of environmental pathogen risk based on our living and working environments. If you work in an office with private offices its one risk level, if you work in cubicles another risk profile, and if you work in the open-style offices (desk to desk) that is common in startups in the SF Bay Area, there is still another risk profile.
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And if you have children in any kind of school environment, every virus within a 100mi radius regularly passes through your house as if you were running a Wuhan lab. 
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Neo
#181
It’s was difficult to hear everything since the audio of that VitaDao podcast was poor, but I think Dr Salmon confirm that the marmosets do live in condition that are similar to your first post here:
The part about
he says that actually, the human environments are probably a lot more like the marmoset environments than “wild” environments.
I believe was referring to that the marmosets - were claimed to - (a) have “real/normal” social relationships and interactions with each other and (b) that the marmosets amount of as lib access to food and the degree of that vs an optimized calories intake is more similar to what humans have in our day to day real world (vs mice ad lib that night over eat even more than marmosets/humans).
I do not believe that the podcast ever said that the marmosets where exposed to pathogens anywhere close to what humans are in normal life
—
There was some hand waving about that white blood cell proportions might not have been impacted that much by rapa, but I believe he also said that they have not checked for immunosuppression levels (why not?)
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These people were not transplant patients and were not taking immunosuppressants: they had lymphangioleiomyomatosis, a disease caused by mutations in the mTOR signaling pathway that give them hyperactivated mTOR, with the lungs affected. Hyperlipidemia is not expected outside of rapa in these patients.
You describe this as a “consistent form of grapefruit,” but AFAICS these are not a consistent form of grapefruit: they’re just ground and dehydrated grapefruit peel, not standardized for furocoumarins or anything else. I would therefore expect tham to have the same batch-to-batch variability in furocoumarin content as the underlying fruits do. And on top of that, this paper found extremely little or zero furocoumarins in grapefruit peel: they’re largely in the flesh:
(GF-I-1, GF-I-2 and GF-I-4 are specific furocoumarins).
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Jjazz
#185
You are absolutely correct that there is likely batch to batch variability in this or any unstandardized grapefruit supplement. These are “consistent” for me in the sense that I can buy ten bottles from the same lot, this will last for a year or two, and the effects should be similar until I buy from a new lot.
Regarding the furanocoumarin content of peel, other references show that grapefruit peel has higher concentrations than the flesh. It probably depends on many factors, like the specific variety, ripeness, storage, etc. From this paper:
“Similar to the diversity of compounds, higher compound concentrations were generally found in peel than in pulp (Figs 2 and 3).” Note the difference in y-axis scales for Figures 2 and 3.
Figure 2:
Figure 3:
Overall, even without standardization, I believe a grapefruit peel supplement can be a more consistent way to inhibit CYP3A4 vs. juice or fresh fruit. Once you have found a dose regimen that achieves your desired blood concentration or effect, you can expect it to be relatively consistent the next time you use the same product from the same lot.
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There are several studies showing that repeat BCG protects against multiple types of infections which in itself increases lifespan (as well as increasing lifespan by reducing cancer risk) so that is the low hanging fruit. I posted about how to take it orally which is IMO safest and most convenient.
UTIs are common in older people particularly older women who take daily rapamycin. There are several vaccines\immunotherapy treatments against the most common bacteria that cause utis. Uromune MV140 is the best and is specifically tested on people taking immunosuppressive drugs. The same company is trialling a vaccine against respiratory infections MV130 and it is going well, but it is not approved yet.
Matt discusses the rapamycin marmoset study in his latest video - queued up here:
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I’ve been wondering about that “inhibit MTORC-2” issue and found several references that Rap does not directly inhibit MTORC-2 but does disrupt it in other ways. So I’m a bit confused on this 
Rapamycin is an acute inhibitor of mTORC1 but not mTORC2, and kinase inhibitors generally target both mTORC1 and mTORC2. Hence, whilst the role of mTORC1 in aging is relatively well defined – rapamycin is well established to extend the lifespan of mice – the study of mTORC2 function has been limited by a lack of specific mTORC2 inhibitors. This is complicated by the fact that chronic rapamycin treatment disrupts mTORC2 in a cell-type and context specific manner. For example, chronic rapamycin disrupts hepatic mTORC2 in vivo, leading to glucose intolerance and insulin resistance; attributed to mTORC2 as Rictor deletion alone also induces hepatic insulin resistance.
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I am not sure anyone has a definitive answer to your question.
My own experience from taking rather high doses for almost 3 years is:
It does seem to delay wound healing, papercuts, etc., but does seem to affect my overall immune system in a positive way. Again, I am 83 and I have caught nothing including Covid in the last three years despite exposure in places that are relatively high risk.
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Yes, rapamycin doesn’t inhibit mTORC2 directly. However, chronic rapamycin therapy inhibits mTORC2 indirectly. That’s why it’s important to not take it too frequently in too high doses, or else it will start inhibiting mTORC2 too much and cause side effects like e.g. glucose intolerance and increased lipid levels.
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George
#192
I think you will need better mTOR inhibitors without the side effect. Even at 6 mg/week, I suffer enormous pain from mouth sores most of the time. Last cycle, the sores lasted a full two painful weeks. Can’t imagine a higher dose.
The problem is that the side effects come from inhibiting mTOR.
