#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.

#139

The failed MSA trial seems to show that BBB crossing is important and that shared mitochondrial effects, if any, are not enough.

#140

This could be in part the issue that if the cells are not functioning well enough then even an mTOR inhibitor won’t get mitophagy to do its job properly.

You are probably right that getting through the BBB is better than not getting through it.

#141

Its interesting… when I spoke with Adam Salmon of UT Southwestern on the marmoset rapamycin study he said they do see BBB penetration with rapamycin, though the exact level he could not specify.

I think generally it does seem to cross the BBB at some level, though probably quite a low level. Rapamycin and the Issue of Getting Through the Blood Brain Barrier

But - I also have a supply of Everolimus (its easy to buy a bunch of 10mg tablets of Zydus Everomus) which I plan to alternate with rapamycin at some point.

#142

Yet Attia claims that Rapa drives down the alpha beta 42/40 ratio in his patients… I’m not sure its fair to define neuroprotection by the seziure study. Neuroprotection could also be defined by maintaining the integrity of the BBB. Sabitini admits that Rapa crosses the BBB in mice but poorly and only at high dose. That seems to generally be the case with Evrolimus as well although some of your references suggest it may be marginally better but I have yet to see a dosage controlled comparison between the two. Obviously it would be difficult to measure sirolimus and everolimus in CSF as part of a trial that was simply asking this question.

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#143

What we know for sure is that 1 mg/day of sirolimus does not cross the BBB in humans. Zero. Niet. Nada. Nothing. That’s the conclusion of the MSA and CARPE DIEM trials.

Does it cross the BBB at higher doses? Maybe. Maybe not.

We also know that everolimus is better at crossing the BBB than sirolimus but we don’t know by how much.

Yes the seizure studies don’t show neuroprotection but I interpret them as “At the usual doses, everolimus can be effective in the brain of humans and rodents while sirolimus is not”.

Similarly, everolimus is FDA approved for some kinds of brain tumors (and is used off-label for some other brain tumors) while sirolimus is not. This is at their DDD so a few mg daily.

To me, all the evidence points to rapamycin not engaging with brain mTOR whether this is for Alzheimer’s, MSA, seizures or brain tumors. At low doses or “normal” doses.

On the other hand, use in seizures and brain tumors + rodent data suggest that everolimus does engage with brain mTOR at the usual doses.

Or did I make a mistake in my reasoning? I’m not trying to “defend” everolimus, just to understand if it has potential or not.

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#144

Never say never… Published this month:

Short-term Sirolimus Treatment Restores Hippocampus and Caudate Volumes and Global Cerebral Blood Flow in Asymptomatic APOE4 Carriers Compared with Non-carriers 2025

:thinking:

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#145

yabut…

  1. 1mg/day is not the usual dose for dementia or longevity…

  2. I have not seen a human study showing Evro is better at crossing the BBB than siro in humans. One would have to dose such that serum levels were similar between the two drugs and then measure CSF levels. That would tell me their relative efficiency of crossing the BBB.

  3. In my opinion neuroprotection in a seziure disorder does not = crossing the BBB or engaging with brain MTOR

  4. The FDA is using the same data we are. I think it has been biased by only studying Evro and not comparing the two head to head (explaining Evro approval for some brain cancers).

#146
  1. Yes.
  2. Yes. I hope one of the ongoing trials will look at that (I didn’t check).
  3. How could everolimus protect from seizure and reduce neuroinflammation without crossing the BBB? And why would sirolimus fail to do both?
  4. It’s not only the FDA but also the clinical practice: offlabel use for brain tumors seems to prefer everolimus. Could be herd mentality though.
#147

By improving mitochondria more generally and those mitochondria being spread around.

#148

But why sirolimus does not at the same dose?

#149

I dont have the time to read up on this at the moment so i dont have an answer, sorry.

#150

No worries. The sources are there: Everolimus instead of Sirolimus / Rapamycin? Anyone else trying? - #136 by adssx

For me, they invalidate your hypothesis.