Rapamycin and the Issue of Getting Through the Blood Brain Barrier

This is sufficiently large cohort to demonstrate clearly that Rapamycin fundamentally does cross the human BBB. It’s been shown in countless mice and rat models, but few human studies…getting a craniotomy isn’t much fun unless you have few choices as a recurrent cancer patient.

The amount crossing matters less per se than mTOR suppression in target cells (out of our control other than dosing). Of course, for those Pharma companies looking to improve permeability, then yes, they would be studying rapalogs to further enhance.

The study showed directly that mTOR suppression was correlated with Rapamycin dosing, so perhaps simply passive diffusion.

I am with you, inclined to take higher doses until I see see some glucose/lipid dysregulation. The oncologist said to me “that’s when you know it’s working”.

From a human perspective, we are flying blind!

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Well, fortunately, or unfortunately, I am old, so I am willing to take more chances than I would recommend to a younger person.
I have watched enough Dr. Brad Stanfield videos on Youtube(LOL) to think he wouldn’t lend too much credence to this article. Also, there is not much actual data available at this stage.
I wish you and all the others and all the others here taking this journey the best. May, we all meet on the other side of 100.

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This is all I’ve found so far on Rapamycin/BBB and HUMANS.

Humans don’t readily volunteer for craniotomies.

The fact that there are so many studies showing Rapamycin passage into the brain of mice/rats, also is supportive.

I’ve calendarized our utopian meetup.

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Here’s a paper (2014) reviewing various pharmacological approaches to treating recurrent glioblastoma.

Molecularly targeted therapies for recurrent glioblastoma: current and future targets (UCSF)

“Sirolimus—Given its large natural structure, there was initial concern that sirolimus might not be able to traverse the BBB; however, sufficient levels of sirolimus can be found in brain tumors when
administered at therapeutic doses (17)”

Reference 17 is the paper on Glioblastoma posted above from 2008.

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Craniotomie is not required.

I have posted this before;

PET scan

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@MAC great find - thanks for posting. From that paper you added, the 2014 (Molecularly targeted therapies for recurrent glioblastoma: current and future targets (UCSF)), I found this paper particularly interesting with regard to the rapalog “Everolimus” - which people here are starting to take instead of (or in addition to) rapamycin. It seems that Everolimus might be particularly good at passing through the Blood/Brain Barrier (BBB).

Everolimus — Everolimus is a specific mTOR inhibitor with lipophilic properties that allow it to readily traverse the BBB. The use of everolimus with bevacizumab as a combined modality therapy for newly diagnosed glioblastoma has shown some efficacy; the PFS compared favorably to previous reports of standard radiation and temozolomide therapy.(47).

The referenced paper (47) is this paper:

Phase II study of concurrent radiation therapy, temozolomide, and bevacizumab followed by bevacizumab/everolimus as first-line treatment for patients with glioblastoma.

Full Paper here: https://www.hematologyandoncology.net/files/2013/05/ho0412_hainsworth1.pdf

Note: For people interested in learning more about the rapalog (acts like rapamycin) drug called everolimus - see this discussion thread: Everolimus instead of Sirolimus / Rapamycin? Anyone else trying?

In it, it states:

Conclusions: The use of bevacizumab and everolimus as part of first-line combined modality therapy for glioblastoma was feasible and efficacious.

Additionally, from the paper:

Four weeks after the completion of radiation therapy, patients began oral everolimus 10 mg daily, and continued bevacizumab every 2 weeks; therapy continued until tumor progression or unacceptable toxicity.

The dose of everolimus was modified on the basis of either hematologic or nonhematologic toxicity. Everolimus was interrupted if grade 3 or 4 toxicity occurred, and was held until the toxicity improved to grade 1 or less. At that time, dosing was resumed with a 1-level dose reduction (5 mg orally once daily). Patients were monitored for development of hyperlipidemia or hyperglycemia; if these events occurred, appropriate medical management was initiated.

Patients with objective response or stable disease began treatment with concurrent bevacizumab and everolimus. Patients were reevaluated at 8-week intervals with MRI scans until tumor progression was documented.

Interestingly, researchers have been testing Everolimus with many other cancer drugs, where they are finding that not only does Everolimus cross the blood brain barrier well, but it also helps other cancer drugs enter the brain and target tumors better (it seems). Here are some examples:

The research team at the Institute of Cancer Research, London, led by Professor Chris Jones, found that a drug called everolimus could enhance vandetanib’s capacity to pass through the blood-brain barrier in order to treat the cancer.

Combining the two drugs increased the amount of vandetanib in the brains of mice with DIPG by 56 per cent. The researchers also found that the treatment extended survival in mice by 14 per cent compared with those receiving a control treatment.

Source: Scientists identify new drug combination for children with incurable brain cancer

And:

Our results show that the efficacy of dasatinib treatment of PDGFRα-driven HGG was enhanced with everolimus and suggest a promising route for improving targeted therapy for this patient population.

Source: Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma

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They are quite similar pharmacologically. Not nearly as many longevity papers in mice, as with Rapamycin.

Thoughts?

Sirolimus and everolimus in kidney transplantation

https://sci-hub.se/https://doi.org/10.1016/j.drudis.2015.05.006

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I think Everolimus bears a closer look - perhaps as something we alternate with rapamycin, or perhaps dose simultaneously with rapamycin, or perhaps as a replacement for it.

There won’t be many mice studies or longevity studies (if any) because Everolimus is so close to rapamycin in terms of molecular structure (and also from a functional standpoint its almost identical), and because it has only recently gone off-patent (so no motivation by drug company to test in anti-aging, and too expensive for academic labs to have used in their trials/research).

Here is what Matt Kaeberlein has said about it:

rapaOrEverolimus2

Detailed discussion on Everolimus here: Everolimus instead of Sirolimus / Rapamycin? Anyone else trying?

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Here’s one longevity study Everolimus, transgenic EGFR mice.

10 mg/kg/day

Everolimus prolonged survival in transgenic mice with EGFR-driven lung tumors
https://sci-hub.se/10.1016/j.yexcr.2014.04.012

“The median survival time of the everolimus-treated group (58.0 weeks) was significantly longer than that of the vehicle group (31.2 weeks)” That’s 85% on this metric

Interesting, mTOR and pMTOR don’t see as suppressed compared to vehicle in vivo? Wait what, not mTOR?

" Everolimus suppressed pmTOR and pS6 but not p4E-BP, and increased pAKT (via negative feedback) in vitro (Fig. 1C). Also, everolimus suppressed pS6 but not pmTOR and p4E-BP in vivo (Fig. 3B). Conceivably, everolimus may act on different signaling pathways in vitro and in vivo. Our results using transgenic mice suggest that marked suppression of pS6 by everolimus might be important in this respect"

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New poster at the American Aging conference this coming week:

Wednesday, May 18th

Neuronal mTOR signaling controls peripheral metabolism

1:35 PM-1:55 PM

DescriptionNeuronal mTOR signaling controls peripheral metabolismStacy A. Hussong1,2 and Veronica Galvan1,21University of Oklahoma Health Sciences Center 2Oklahoma City Veterans Health Care System, Oklahoma City, Oklahoma The mechanistic target of rapamycin (mTOR) is a central regulator of cellular and organismal metabolism. Reduction of mTOR signaling by rapamycin alters organismal metabolism and increases lifespan and healthspan. Neurons regulate many aspects of metabolism. To test the hypothesis that reducing mTOR signaling in neurons would impact critical aspects of metabolism cell non-autonomously, we genetically reduced mTOR complex 1 (mTORC1) by targeting its obligatory component Raptor in neurons of adult mice. Reduction of mTORC1 complex formation in neurons of adult mice by 35% or 60% did not impact body weight nor glucose and insulin tolerance, but increased liver gluconeogenesis and glycogen accumulation in skeletal muscle in association with enhanced exercise endurance and absent post-exercise hypoglycemia. While metabolic impact of mTORC1 attenuation could be partially recapitulated by mTORC1 knockdown in hypothalamus, exposure of muscle cells to serum from neuronal mTORC1 knockdown animals recapitulated in vivo changes in gluconeogenesis and glycogen metabolism, suggesting that circulating factor(s) mediate, at least partially, the cell non-autonomous peripheral impact of mTORC1 attenuation in neurons. Moderate (35%) but not profound (60%) mTORC1 knockdown in adult neurons also increased brain glucose metabolism and cerebral blood flow, enhanced spatial memory, and upregulated PGC1α. Thus, in addition to regulating cognitive function in a non-linear fashion, presumably in a cell-autonomous manner, mTORC1 signaling from neurons regulates basal and exercise metabolism cell non-autonomously in adult mice. Ellison Medical Foundation, Owens Foundation, Bailey Family Alzheimer’s Fund, VA 1 IK2 BX003798-01A1, NIA5T32-AG021890, 1 I01 BX002211-01A2, JMR Barker Foundation

Speaker

Source: 2022 AGE Program

Thanks. I attended AGE (virtually) and saw that poster.

Does anyone have solid info on the IC50 of rapamycin – for inhibition of either mTORC1 or mTORC2 – in neurons (or other parts of the brain)? Hussong’s work could help guide dosing.

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I’ll add a PET scan is about $100-200 in India. @Joseph

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Quote Source:

mTOR drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13057

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Ive been using 5mg of everolimus with 500g metformin once per week for 9 months

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Very interesting. Everolimus molecule size is about 5% bigger than Rapamycin. And there’s no difference in charge, so all other things being equal you’d expect rapamycin to cross the BBB marginally more easily

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Any side effects? Though that is still a pretty low dose, equivalent to about 3 mg sirolimus. Do you plan to go higher?

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5 posts were split to a new topic: Rapamycin for Eyes

desertshores, you may have shared this elsewhere, but can you share your aggressive rapamycin dose?

I started at 5mg/week with no amplifiers other than EVOO.
Then worked up to every 14 days at 20 mg. with ruby red grapefruit juice and EVOO. That proved to be too much as I got diarrhea every time at that dose. Since then after experimenting with doses that did no cause subjective side effects I settled on 5mg/ weekly with Bioperine, EVOO and RRGGJ. This I tolerate quite well and probably gives me an effective dose equivalent to 15 - 30 mg weekly.
The non subjective problem is my current ferritin levels are below normal. This may not be because of rapamycin, it may be because I am getting too old to give blood twice a year. Right now I am off rapamycin for awhile until I get my ferritin levels back into the normal rang.

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Thank you for the reply. This is very interesting. I was on 24 mg every other week and just switched to 12 mg every week to experiment and see how I feel. I’m 58 years old and thinking of adding GFJ to the regimen. Interestingly enough my ferritin has been below normal the past two labs. I don’t each much iron in my diet but in the past year it has been in the lower end of normal but still in the normal range until my two most recent labs.

I’m not too worried given I have been following Mangan’s advice and wanting a ferritin number towards the lower end and I also donate blood every three to four months.

Question for you. What is your GFJ protocol? How much GFJ and when in terms of before/during/after you take the rapamycin?

Thanks

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