#119

I am much newer to taking rapamycin than most here, but I’m already leaning the same way for the same reason. I’m hesitant to take rapamycin more frequently than once every 2 weeks, and I have still not regained the strength/muscle I lost when in the ICU in 2021.

I speculate that one high, weekly burst of everolimus on a light cardio day would reduce anabolic resistance and prepare my muscles for more effective hypertrophy training the rest of the week.

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#120

After using rapa for about 6 months, I tried Everolimus at 10 mg weekly for about 6 months. After reading Mannick “mTOR inhibition improves immune function in the elderly” I expected it to work as well as or better than rapa. But I didn’t notice any effect, nor did my friend who used it for at the same dosage for about the same length of time. Maybe the dose was too low.

For me rapa had a noticeable effect with reduced systemic inflammation, improved skin appearance, and stabilized body weight after weight loss. Currently I take 5 mg weekly with GFJ.

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#121

Recently academics at the University of London, UK, explored the effects of mTOR inhibitors on the effects of nematode senescence. The conclusion was that the rapamycin analogue, tesirolimus, was similar to rapamycin in extending lifespan, whereas everolimus was less effective.

I don’t think it’s fair to say that everolimus is inferior to rapamycin, because nematodes are so different from humans. What’s everyone’s opinion on this?

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#122

Based on what I know, everolimus has a much shorter halflife than Rapamycin so it clears your system quicker. If the nematode data is similar to human data (a big IF) then it would imply that you don’t want a short quick spike of MTOR inhibition but a more prolonged exposure in your system that declines slowly over time. I feel that this is most probably true.

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#123

Interesting experience! Did you take everolimus with GFJ as well? The DDD of everolimus is 10 mg vs 3 mg for sirolimus so does it mena that 5 mg of sirolimus with GFJ would be 17 mg of everolimus with GFJ?

#124

Is anyone taking everolimus? It looks interesting as it crosses the BBB + shorter half-life + seems better than rapamycin for neuroprotection in longitudinal studies:

But does it have the same safety profile as rapamycin?

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#125

When I took 10mg everolimus per week and felt weak within a few days. When I took 6mg rapa per week and did not experience this reaction. now I returned to 6 mg/week rapa again.

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#126

Thanks for the feedback. According to the WHO the daily defined dose of everolimus is 1.5 mg so half the sirolimus dose: ATCDDD - ATC/DDD Index

If this is correct and transferable to “longevity” doses then your 10 mg dose of everolimus would be equivalent to 20 mg of sirolimus?! This might explain the fatigue?

@John_Hemming what are your thoughts on everolimus vs sirolimus ?

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#127

I haven’t looked at everolimus. I like Rapamycin itself because there is quite a lot of data on it. It would I think be helpful to have a shorter half life, but as far as now is concerned Rapamycin is what I am using when I take it and there would have to be a really good reason for me to look at an alternative.

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#128

On the dosing - let us remember, that the famous Mannick study used everolimus, not sirolimus. On these boards we often tend to conflate the two when it comes to the results of this study. And I often see the justification for rapamycin dosing protocols also based upon this study - it established the once weekly timing (in one of the arms) and found the 5mg/1-week to be the most effective with least sides. But again, this is for everolimus. From this many somehow found an indication for 6mg/1-week of rapamycin as suitable. But if everolimus has a much shorter half life, how does the once a week optimal timing for everolimus translate to a supposedly optimal also once a week timing of rapamycin? And if there’s a significantly different dosing effect between them, how does the optimal 5mg everolimus dose translate to a 6mg optimal rapamycin dose? Btw., let us note that there has been no adjustment of dosage for weight in the Mannick study. And there has been no weight adjustment in the mice ITP as far as I know - though one could argue that mice are mostly very similar in weight (plus if the rapamycin is incorporated into the chow, how do you control for different mice eating different amounts, depending on individual appetite). But for dogs and cats, the rapamycin dose is adjusted for weight (0.15mg per kg), because there are significant weight/size differences among cats and dogs both. So my question is where do human beings fall in this consideration? Clearly less uniform compared to mice, but certainly not as widely divergent as dogs (think mastif vs daschund), if we ignore the obesity factor. At the same time, there is significant size difference between men and women - perhaps that accounts for part of the difference in outcomes in the PEARL trial between men and women at the same dose, which did not account for weight/size (there were some significant effects in women at the highest dose, while no effect reached significance in men - perhaps due to size/dose effect?). Should we account for size in rapamycin and everolimus doses in humans a la dogs, or not, a la mice?

Many questions, few answers.

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#129

I haven’t seen studies compare everolimus and sirolimus directly with respect to their ability to cross the BBB. Everolimus frankly doesn’t cross well and may not be significantly different than sirolimus IMHO.

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#130

I need to do more research but I found: Everolimus and Sirolimus in Transplantation-Related but Different 2018

One of the key differences between sirolimus and everolimus in these studies was that at therapeutically relevant concentrations everolimus, but not sirolimus, could distribute into brain mitochondria [34, 50]. Interestingly, at very high concentrations sirolimus could also be found in brain mitochondria and when this was the case, sirolimus also was able to antagonize the negative effects of cyclosporine on mitochondrial metabolism. In addition, at concentrations close to the therapeutic range, sirolimus increased while everolimus decreased cyclosporine concentrations in mitochondria [34].

Everolimus isn’t super brain penetrant but is approved for some kind of epilepsy so it does affect the brain: https://www.sciencedirect.com/science/article/abs/pii/S0028390820303658

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#131

The key question for the brain is the extent to which mitochondria are shared between cells in the brain and the rest of the body.

If they are shared in a significant manner then you can improve brain mitochondria (gradually) by improving the mitochondria elsewhere.

Given that exercise appears to help cognition and that would be the mechanism most likely to cause this effect I think it is possible to improve the brain via the rest of the body. The response would be slower, but still there.

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#132

What? I’m not aware of mitochondrial “sharing” between any cells except perhaps multi nucleate cells in the liver and muscle.

#133

I don’t know about whole mitochondria sharing between cells or tissues and merrily crossing the BBB - how would this work, lol - but the same molecules, perhaps the drug by itself doesn’t cross the BBB, but its metabolites could affect all mitochondria, including in the brain - isn’t that how the gut-brain connection works?

Now the suggestion that sirolimus can affect brain cells, but only if at sufficiently high dose is very intriguing. How does that work, what is the mechanism? So maybe we want that dose for our rapamycin intervention? From the start, the big limitation and unknown has been how to establish the right dose and protocol for taking rapa for longevity purposes. What biomarker, or what effect measure do we use? No real clues, other than perhaps dosages used by transplant patients are too high (though that is often confounded by concurrent use of other drugs and the disease pathology itself). Well, how about using the marker of “high enough to cross the BBB”? Obviously people have different goals with rapa, not simply longevity, like perhaps ameliorating some pathology, so that’s another indication and dosage. But that’s very interesting - sirolimus can affect the brain directly!

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#134

Perhaps I misunderstood. Still having trouble imagining products of mitochondrial oxphos being shared between cells. NADH, ATP, etc are cytoplasmic and mitochondrial molecules and don’t circulate and get taken up by cells ie they are reduced or phosphorylated within the cytoplasm.

Re sirolimus and CNS efficacy, this is why some here administer large sirolimus doses infrequently (q 14 or 21 days) so as to affect some crossing of the BBB. I’m interested in this but it isn’t clear that Rapa needs to cross the BBB to affect dementia so It may be a non issue (since dementia really is the brain aging target).

#135

The body has a TCA homeostasis in serum. TCA = Tricarboxylic acid … aka … citrate

#136

I did more research on everolimus vs sirolimus, with neuroprotection in mind. I’ll repeat some papers already posted in this thread.

We know that sirolimus does not engage with brain mTOR (at least in MSA patients):

On the other hand: Sirolimus, but not the structurally related RAD (everolimus), enhances the negative effects of cyclosporine on mitochondrial metabolism in the rat brain 2001

In addition RAD, but not sirolimus, distributed into brain mitochondria.

Everolimus and sirolimus are very similar drugs: An overview of the efficacy and safety of everolimus in adult solid organ transplant recipients 2022

Everolimus was developed to improve the pharmacokinetic (PK) characteristics of its analog, rapamycin, also known as sirolimus. The introduction of a hydroxyethyl moiety at position 40 alters the chemical properties and PK of everolimus compared with sirolimus. Everolimus is more polar and hydrophilic, exhibits a 60% higher bioavailability, and reaches a steady state faster than sirolimus (4 days vs 5–7 days) with a shorter half-life (28 vs 62 h) following oral administration. As a result of this shorter half-life, everolimus is dosed twice daily, which facilitates better dose adjustment and improved maintenance of target trough concentrations (C0) compared with sirolimus.

Everolimus causes slightly less glucose disruption: Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system 2016

Further, we find that the FDA-approved rapamycin analogs everolimus and temsirolimus efficiently inhibit mTORC1 while having a reduced impact on glucose and pyruvate tolerance.

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Fewer studies in humans vs rapa: Targeting ageing with rapamycin and its derivatives in humans: a systematic review 2024

But the Novartis trial by Mannick showed that everolimus (RAD001) “enhanced the response to the influenza vaccine by about 20% at doses that were relatively well tolerated”: mTOR inhibition improves immune function in the elderly 2014. It’s a pharma trial, so I give it way more weight. 6 weeks of treatment with either 0.5 mg once daily or 5 mg once weekly.

Mannick published this comparison in 2023: Targeting the biology of aging with mTOR inhibitors

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No data on rodents, indeed. In drosophila (DrugAge) and C. Elegans (Characterization of Effects of mTOR Inhibitors on Aging in Caenorhabditis elegans 2024), everolimus is weaker vs rapa.

In humans, everolimus is approved for some type of seizure while sirolimus is not and does “not significantly reduce seizure frequency”: Everolimus as adjunctive therapy for tuberous sclerosis complex-associated partial-onset seizures 2019. See also: Everolimus is better than rapamycin in attenuating neuroinflammation in kainic acid-induced seizures 2017

Everolimus-eluting stents are a bit better than sirolimus ones: Safety and efficacy of everolimus- versus sirolimus-eluting stents: A systematic review and meta-analysis of 11 randomized trials 2013 (“treatment with EES significantly reduced the risk of repeat revascularization and definite ST compared to SES. We found no significant differences in the risk of cardiac death or myocardial infarction.”)

In other conditions (organ transplant and tumors), either I couldn’t find a comparison or they seem to have similar outcomes.

There’s one longitudinal study pointing to everolimus being 2x more protective than sirolimus in PD: Everolimus instead of Sirolimus / Rapamycin? Anyone else trying? - #124 by adssx (these two papers are actually the same, conference version and peer-reviewed published version)

In terms of ongoing trials for aging and/or neuroprotection, we have:

  • CARPE_DIEM (NCT04200911), Texas San Antonio, 2020–2022, AD: sirolimus 1 mg/day (COMPLETED)
  • REACH (NCT04629495), Texas San Antonio, 2021–2026, AD: sirolimus 1 mg/day
  • RESTOR (NCT06658093), Texas San Antonio, 2025–2029, Aging: sirolimus vs everolimus
  • NCT06727305, Texas Southwestern, 2025–2027, Aging: sirolimus vs everolimus (0.5 mg, 1 mg, or 2 mg/day)
  • ERAP (NCT06022068), Karolinska, 2023–2025, AD: sirolimus 7 mg/week
  • EVERLAST (NCT05835999), Wisconsin, 2023–2026, Aging: everolimus 0.5 mg/day vs 5 mg/week vs placebo
  • RAP PAC (NCT05949658), Wisconsin, 2024–2028, Aging: sirolimus vs everolimus (5 mg, 10 mg, or 15 mg/week)
  • RapaLoad (NCT06789900), Odense, 2024–2025, Menopause: everolimus 5 mg/week

CARPE_DIEM posted their results a few weeks ago (even though the trial ended in 2022!): ClinicalTrials.gov Hard to interpret without a placebo, and they haven’t published a paper yet but cognition scores decreased after 8 weeks of rapa and the blood-brain barrier penetration of rapa was exactly 0 ng/mL. Not great. And yet they started a subsequent trial (REACH) but I think they started it before they got the CARPE_DIEM results. Still, I find it “interesting” that the University of Texas Health Science Center at San Antonio launched an everolimus vs sirolimus trial after two trials of sirolimus only…

My conclusion: rapa doesn’t seem to offer potent neuroprotection and does not cross the BBB. Everolimus might be a bit better in that regard (BBB crossing + safety profile + neuroprotection), but the evidence is weak. Wdyt @John_Hemming @DrFraser?

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#137

What we don’t really know is the limits on the sharing of mitochondria. If we are aiming to improve mitochondria and do it outside the brain there is evidence that the mitochondria sharing effects the brain. Hence I am not particularly worried about the BBB.

#138

Thanks for pulling so much information together! Reading this causes me to have some doubts about rapamycin dosing and benefits vs everolimus. I’ve often wondered where the evidence actually suggests intermittent dosing vs low every day doses. I’m glad to see some trials are exploring low daily dose vs intermittent with everolimus.