also interesting in wikipedia
What might come as a surprise is that mTORC2 signaling is also regulated by mTORC1. This is due to the presence of a negative feedback loop between mTORC1 and insulin/PI3K signaling.
So will rapa inhibition of mTORC1 upregulate mTORC2 because of increased insulin/PI3K signaling? Any experts?
Here’s an interesting paper on negative impact of mTOR2 blunting.
Inactivation of mTORC2 in macrophages is a signature of colorectal cancer that promotes tumorigenesis
“In this work, we have shown that blockade of mTORC2 in macrophages leads to aggravated disease of colitis-associated CRC in mice and humans. This was partly due to the protective role of mTORC2 during colitis to dampen inflammatory damage, a well-known driving force for the development of CRC. We now describe a suppressive role of mTORC2 in macrophages for an inflammation-based tumor model of CRC. Similarly, mTORC1 has anti-inflammatory properties by stimulating production of IL-10 in DCs that protect the colon from chronic inflammation (22). Hence, global inhibition of mTORC1 and mTORC2 in cancer patients could have adverse inflammatory effects on the immune system by promoting tumorigenesis, as seen with a second-generation mTOR inhibitor in our mouse model. Thus, altering the innate immune system and its inflammatory response, as shown here, can be driving forces of cancer development. The potential unfavorable activities of second-generation mTOR inhibitors might especially be important for inflammation-associated tumors, where mTORC2 activation in macrophages seems to reestablish tissue homeostasis after colon damage. Instead, our work indicates activation of mTORC2 in macrophages as a therapeutic possibility in CRC”
They did NOT use Rapamycin, but a dual TOR1/TOR2 inhibitor, AZD8055*
“Our results at this point showed that low mTORC2 activity in macrophages was associated with a poor outcome in CAC and thus raised the possibility that pharmacological inhibition of mTORC2 might actually increase colorectal tumorigenesis. Therefore, we subjected WT mice to the AOM/DSS model and treated them with the second-generation mTOR inhibitor AZD8055 (Figure 8A). On day 6 after the last DSS cycle, we performed colonoscopy and observed significantly increased tumor numbers in the AZD8055-treated animals”
*"AZD8055 is a potent and orally bioavailable ATP-competitive inhibitor of mTOR kinase with an IC50 of 0.8 nM. It inhibits both mTORC1 and mTORC2. AZD8055 shows excellent selectivity (1,000-fold) against all class I PI3K isoforms and other members of the PI3K-like kinase family. Furthermore, AZD8055 showed no significant activity against a panel of 260 kinases at concentrations up to 10 µM [1].
The serine/threonine kinase mTOR is crucial for cell growth and proliferation. It regulates cap-dependent translation through the mTORC1 complex and Akt activation through the mTORC2 complex. AZD8055 inhibits the phosphorylation of mTORC1 substrates p70S6K and 4E-BP1 as well as the phosphorylation of the mTORC2 substrate AKT. AZD8055 potently inhibits proliferation, induces autophagy and apoptosis in different cells. In vivo, AZD8055 induces a dose-dependent pharmacodynamic effect on phosphorylated S6 and phosphorylated AKT and results in significant tumor growth inhibition and/or regression in xenografts representing a broad range of tumor types [1-4]."
Listened to a Q&A with Matt K, Dr B and Dr Green
seems like Green is taking 12 mg on two consecutive days and then waiting two weeks
Dr B is taking 1 mg every other day now! A big change from previous reports
Anyone else watch this?
Even the “rapamycin gurus” have no idea human translation protocol for human lifespan extension.
A brief Peter Attia (who I follow and respect his ability to cut through the smoke) blurb at introduction…“here’s a drug, we have NO biomarker and NO good human clinical data”. But even he stated approx 20% of his patients are taking it under his supervision.
Dr G with his hundreds of patients, is NOT measuring blood Sirolimus.
Dr B made an interesting comment when questioned as to whether Rapamycin is an anti-aging drug or simply delays cancer? He said it extends lifespan even in animal models that don’t get cancer? I know there are some animal species that have very low cancer or almost none (eg. naked mole rats), but a study with rapamycin?
Anyone know of such a model study?
There are rapamycin gurus in the sense of understanding the science but no one has access to a human RCT since there aren’t any.
We’re relying on mice , renal transplant patients, a couple of small human trials, and anecdotes.
@MAC , FYI: the Kaeberleins said in their email with a link to this video that they would appreciate not sharing the link. I posted a link for the previous webinar and was reminded not to. Still, I want a discussion of it.
Sorry my bad, jumped the gun. Freedom of the press.
Any thoughts as to why they want to keep this under wraps? These 3 guys said absolutely nothing really new, proprietary, or shared personal information.
I found the video very enlightening.
Many of us are pure experimenters. We need the information and guidance in this video because as they say in the video, there aren’t many doctors out there willing to even discuss rapamycin protocols. Just recently my cardiologist dropped me as a patient and referred me to another cardiologist. He wouldn’t even discuss it and became very irritated when I even mentioned it. My primary physician didn’t get mad but won’t discuss it. (FYI my primary physicians have always referred me to see a cardiologist every year because when they take an ECG it is a little abnormal because of a childhood illness.)
“do no harm…even by association”
No money in prevention anyway.
My Summary of Discussion 0:00 - 0:30
Discussion of what is an optimal dosing:
Dr. Green: varies by person, stage in life, and reaction to the dosing; he currently does 12mg on each of 2 days in a row, with about a 12 day interval between. He generally recommends a starting weekly dose of 6mg for men and 4mg for women.
Dr. Blagosklonny: conservation of blood rapamycin can vary 10-fold, so the dose shouldn’t be the same for everyone. He considers the 6mg men/4mg women does safe. Animal studies have almost never shown that a higher dose does worse for extending lifespan than a lower dose. So he recommends the highest tolerable dose. More tissues, such as the brain, will have mTOR inhibition at a higher dose. Animal models show that peak levels are important.
Dr. Green judges the results of his dosing for patients by looking at their HOMA-IR (insulin resistance) score since high insulin causes high mTOR.
Do they recommend measuring blood rapamycin?
Dr. Green: yes, high and low levels might be of interest
Dr. B: we don’t know what levels should be for anti-aging. His main guidance would be adjust if there are or are not side effects.
MK: think about different types of side effects, since some take a long time to develop. He would not push higher dosing if someone is already on a high dose (based on community consensus) but has no side effects.
Dr. Green: #1 side effect to be concerned about is bacterial infection
That’s helpful. Sort of. But it makes you very aware of how little we actually know.
Dr Green was VERY quick to respond and jump on bacterial infection as #1 risk/side effect, no real concern for glucose/lipids.
0:30 - 1:00
Are you concerned about hyperlipidemia?
Dr. Green: there is an idea that such lipids are not going into the tissue. And then there is the idea that rapamycin is dramatically decreasing inflammation. But he still like LDL to be 120 or less and HDL in a nice range. He recommends Crestor, which doesn’t cross the blood-brain barrier. Animals studies show very high cholesterol levels at the same time they were clearing cholesterol plaque.
Dr. B: In humans, rapamycin prevents atherosclerosis. Increases in blood glucose happens uncommonly in humans, related to a decrease in insulin due to rapamycin. That way you can be insulin sensitive, but glucose intolerant, much like after fasting.
Dr. Green: He sees a decrease in insulin level in his patients, and wants them to increase insulin sensitivity.
Metformin + Rapamycin
Dr. Green: uses metformin with people who are insulin resistant, but not the insulin-sensitive patients
Dr. B: research on metformin used to be more positive, but now there is complete confusion about the mechanism of metformin. There are like 1000 mechanisms. He agrees about adding metformin for the insulin-resistant. Only one study showed extended lifespan with met+rapa, so there is no real data.
MK: metformin is a dirty drug with many targets, while rapamycin is very clean, with only one target. That makes it hard to know the consequence of taking metformin
Fasting + Rapamycin
Dr. Green: he doesn’t like fasting, but does intermittent fasting. Fasting in mice studies are mostly showing a reduction in AGEs compared to their usual high-AGE diets.
Dr. B: combo is very good for weight loss and possibly longevity. He would add exercise to this combo since fasting can cause muscle loss. Rapa helps maintain healthy muscle.
Dr. Green: In studies, the #1 way to reverse sarcopenia in the elderly is caloric restriction. Reducing mTOR helps maintain healthy muscles.
Dr. B: rapa rejuvenates satellite cells in muscles, increasing muscle strength in aging.
Protein restriction + Rapamycin
Dr. Green: high protein increases mTOR, so he likes a moderate protein diet
Dr. B: depends on age and goal. The only negative of protein is mTOR activation, but all food does that and there is nothing special about protein.
MK: human data shows that for the young, low protein reduces mortality, but in old age, HP reduces mortality. Other studies show HP is not detrimental at younger ages.
Dr. Green: with high supplements of high glycine and cysteine, glutathione levels might be maintained
MK: his intuition is that moderate to high protein detrimental effects, if any, would be offset by rapa, as would most lifestyle interventions that might otherwise raise mTOR.
Dr. Green: lifestyle can override rapamycin, such as in lifestyles that cause insulin resistance, which causes high levels of mTOR
Dr. B: in 2005 and 2007, human studies showed that despite (high?) protein, subjects given rapa did not become insulin resistant
Here is my summary from 1:00 - 1:34 of the 2nd AMA. It is not verbatim, just my understood summary. Does anyone have in problems with some of the things they are saying in the AMA? Mostly it is good info, but I think there are some problems.
Grapefruit juice and Bioavailability of Rapamycin
Dr. Green: discourages GFJ because you want to have a high level initially and have the body metabolizes it to a low level. GFJ will maintain it at high levels. He is concerned about possible increased side effects.
Dr. B: discourages it because other drugs and supplements will also be affected by GFJ. People are doing it to save money.
Compounded Rapamycin
Dr. Green: He prefers Pfizer Rapamune and a producer in India. He is concerned about compounding pharmacies’s products, but likes the powder for topical rapamycin. Studies show the topical decreases senescent cells and SASP.
Dr. B: if you have a powder, people want to make rapamycin (pills) themselves, but he doesn’t want to teach people this. His goal is to change doctor’s attitudes toward rapamycin, and not to encourage people to take it on their own.
MK: topical study was at Chris Sell’s lab at Drexel: Bioavailability of powder was low because of stomach pH. One study of compounded capsules from a pharmacy showed about 4-fold lower bioavailability.
Acarbose, NMN, Berberine
Dr. Green: Berberine is much like metformin. Acarbose: a diabetes drug that is good for those with pre-diabetes; it is an age-extension effect, but it is not a new pathway.
Dr. B: senolytics are unproven as a life extension drug that kills senescent cells. A study showed it extended life span, but not how they did it: killing cells or inhibiting mTOR? Data support is minimal.
MK: most literature on senolytics have to do with their ability to clear cells that are expressing p16, p21, and SA-β-gal and turn off SASP. Whether this is due to reduced mTOR or activated immune cells is unclear. Rapa is more effective, probably both as a senomorphic (turning off SASP) and a senolytic.
Dr. Green: rapamycin in skin has been shown to decrease the production of senescent cells and decrease their inflammation
Followup survey:
MK: maybe another in the next 12 months, and it would be great to do followups annually, but no promises
How do we know mTOR inhibition is not deleterious?
Dr. B: how can something that extends lifespan be harmful?
Dr. Green: wait 20 years, and see how we are doing with rapamycin. If it reduces age-related disease and increases lifespan, how bad can these speculated deleterious effects be? We see some lifestyles around the world that reduce mTOR having a good lifespan effect.
MK: most everyone will benefit from rapamycin, but it is not 100%
Great stuff - thanks so much for posting the summary!
AMA #2: 1:34 - end
Autism
MK: mTOR activation is associated with autism. Some mutations that lead to mTOR hyperactivation are associated with autism. There is good reason to think rapamycin will help with some forms of autism.
What theory of aging do you use to underpin your research?
Dr. Green: Earlier beings like reptiles had minimal senescence. Later animals, such as mammals, had senescence that would lead to aging for the improvement of genetic variation. Animals that die earlier are better able to adapt to a changing world. Senescence supercharged evolution.
MK: Alan (Green) is very much in the camp of programmed aging being evolutionarily beneficial.
Dr. B: hyperfunction theory: the same processes and pathways that drive development growth also drive aging, becoming hyperfunctional.
Dr. Green: these are not conflicting theories
Dr. B: SASP is a typical hyperfunction. Cell hyperfunction eventually leads to organ damage.
Dr. Green: Dr. B’s 2006 paper gives an example of bees: with the same genetic code, different bees can increase their lifespan 10-fold, such as the queen. If animals want to live longer, they can find a way to do it.
Is there a good way to monitor inflammation with blood tests?
Dr. Green: hard to monitor non-bacterial inflammation
MK: Not now, but he is cautiously optimistic in a few years we will have useful blood tests of inflammatory markers associated with aging. Anecdotally, many people taking rapamycin have reduced aches and pains.
Neutrophil reduction is a known effect of sirolimus. Is there is threshold of concern?
Dr. Green: below the normal range is a contraindication (of the sirolimus dose)
Does rapamycin reduce hearing loss and slow graying of hair?
Dr. Green: better at preventing hearing loss at an early stage
Any views on gene therapy, e.g. follistatin and telomerase?
Dr. B: telomerase knockout mice have a greatly reduced lifespan. In humans, there are some genetic diseases with a fault in telomeres, and these people die from bone marrow failure, but this is not typical aging. Telomere length does not limit lifespan. After a long life, say 200 or 300 years, it might be life-limiting.
MK: gene therapy as a life-extending strategy: concerns that it is too early and irreversible.
Dr. Green: would like to target epigenetic changes by genetic therapy
Do older mice show improvements when taking rapamycin?
MK: yes: delay in functional decline, and actually improving immune function, cognition, and in many tissues
Dr. Green: periodontal diseases respond to mTOR inhibition and to the removal of senescent cells, like it is the same thing
MK: rapamycin effects are more impressive than those of senolytics (fisetin, D+Q); clearly there is an overlap between the two approaches
Dr. Green: cardiac studies also show the role of senescent cells in promoting coronary disease. Senolytics and rapamycin do the same thing.
Tinnitus and Rapamycin
Dr. B: he would not be surprised if it would help
Dr. Green: prefers treatment before disease happens
Is rapamycin contraindicated for those who have recovered from active cancer?
Dr. B: it should not be for all. It is used for cancer therapy and prevents cancer.
Dr. Green: having recovered from cancer is a strong indication to take rapamycin. Rapamycin slows angiogenesis and cancer proliferation. It is a strong anti-cancer drug, more at the proliferation level than in the genesis of cancer.
We have our own in house show notes editor!
Has anyone changed anything based on the content of these videos?
Sometimes it is pretty hard to make out what they are saying! I like hearing their different points of view.
Maybe these guys are in a great Ponzi scheme? Lol
Dr Green has built a pretty lucrative practice on the back of Dr B hyper function theory; they are attached at the hip.
I use rapamycin from Tailor Made pharmacy that compounds it. Costs less I think and they have high purity but I’m concerned that it could be less bioavailable according to Matt’s comments.
He seems to say it’s because of stomach ph but why wouldn’t that affect tablets as well. Only specifically coated tablets would be protected.