Thank you for your response. I guess we just have to agree to disagree.
I’m sorry I just find too many references that Cmax for Sirolimus is higher when taken in a fasting state.
Absorption is variably affected by food, especially high-fat meals that decrease the oral bioavailability
The rate at which sirolimus was absorbed was
slower in the presence of food, as shown by a significant lengthening of the time to attain peak plasma concentrations together with a significant reduction in
Cmax (Figure 1, panel B; Table I). The Cmax/AUC ratio
was also decreased when sirolimus was administered
following a high-fat meal.
The systemic absorption of both sirolimus and everolimus is significantly decreased when taken with a meal high in fat.
In the single-dose study in healthy subjects, a high-fat meal delayed everolimus time to maximum concentration (Tmax) by a median 1.25 hours, reduced peak blood concentration (Cmax) by 60%, and reduced area under the concentration-time curve (AUC) by 16% https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1592/phco.22.3.154.33542
Guys - lets pull together some good, specific questions on these topics for Matt Kaeberlein’s Q&A for the rapamycin study participants on March 26th. I think he will be able to clarify the current state of the science in this area.
Well it’s too early to tell the effect it has on my epigenetic age, but I do subjectively feel much better. In fact, since increasing my dose to 20 mg ~twice monthly, I feel almost euphoric from day 2 -5 after dosing. It may be BS or placebo, I don’t care. It has become almost addictive and always look forward to my next dose. I won’t know if there are any measurable results until I complete my current cycle of dosing. I normally complete 100 mg and then take a short break to clear my system and then start the next cycle. I will finish this cycle in about 6 weeks and then have my blood work done and plug the results into the Morgen Levine age calculation spreadsheet and see if there are any improvements. As I have previously posted this spreadsheet calculator does not take cholesterol levels as a marker.
That is also why I previously posted that I do not necessarily take increased cholesterol levels as a bad thing. Recently studies suggest we may have been looking at cholesterol levels in the wrong way.
Dr. Mark Thimineur
“30mg every two weeks for about one year. Experimented with 90mg every 6 weeks (30mg with fresh grapefruit) for about 6 months before”
Like you, I don’t like eating grapefruit. I peel and core my ruby red grapefruit, toss it in the blender with a little water for a frothy grapefruit juice. I read that commercial juicers extract around 80% of the juice, and I’m extracting 100%, so I’m pretty confident that the 3 fold increase is applicable if the juice is prepared this way.
I currently take 7 mg of commercial rapamycin plus one grapefruit about an hour earlier and assume the effective dose is at least 21 mg biweekly.
Have you had any significant adverse effects? Personally, when I upped my dose to 20 mg with grapefruit juice I experienced increased flatulence and loose stools for about 5 days after taking a dose.
Depending on exactly when you are taking the grapefruit juice in relation to the rapamycin - your effective dose of rapamycin could be as much as 3.6 times higher than the dose you think you are taking - so that 20mg could be 72mg, which is extremely high. If you do this on an ongoing basis, you really risk immune system suppression - which could be very bad.
Just want to make sure you know what you are doing when you take the rapamycin and grapefruit juice.
grapefruit juice (GFJ) also can really cause problems with other medications too - so I hope you aren’t taking any other medications.
I take a lower dose weekly but definitely see this effect on ‘dosing day’ and a little into day 2. Can’t think what the mechanism would be but perhaps it is crossing the blood brain barrier?
Endogenous neuroprotection has been shown to be, in part, due to changes in mTOR signalling pathways and the instigation of productive autophagy. Inducing this effect pharmacologically could improve clinical outcomes. One such therapy already in use in transplant medicine is the mTOR inhibitor rapamycin. Recent evidence suggests that rapamycin is neuroprotective, not only via neuronal autophagy but also through its broader effects on other cells of the neurovascular unit.
According to my reading, Rapamycin is mainly an auto-immunosuppressant and an anti-inflammatory drug. The cases where Rapamycin has had an adverse effect, i.e. developing pneumonia, etc. were in patients whose health and immune systems were already severely compromised. Many studies include patients taking 4 - 5 mg daily for more than a year with few adverse effects. That is a higher total dose than I am taking through the “pulsing” protocol.
If you were to use Google Scholar as a search engine and Googled; “Rapamycin and autoimmune suppression” or Googled “Sirolimus and autoimmune suppression,” you will find the results are mostly positive.
Rapamycin is also an anti-inflammatory, which is mostly a good thing.
My main objective with higher dosages of Rapamycin is not to increase lifespan. I believe lower doses are sufficient to achieve that. But, because I am 81 yrs. and in good health, my main objective is to stop and/or reverse cognitive decline. I have not noticed much decline in long-term memory or the ability to solve crossword puzzles or sudoku puzzles, but I have noticed a decline in working memory i.e.: Where did I put that screwdriver, hammer, etc. This causes me to take more time in completing tasks because of time spent looking for things.
Effects of Rapamycin on Insulin Brain Endothelial Cell Binding and Blood-Brain Barrier Transport:
“Rapamycin is an exogenous compound that has been shown to improve cognition in Alzheimer’s disease mouse models and can regulate pathways downstream of the insulin receptor signaling pathway”
There are many other references supporting this to be obtained through the Google search engine.
Look into ketone esters.
This is an older video, published 8 year ago;
“Unconventional But Effective Therapy for Alzheimer’s Treatment: Dr. Mary T. Newport at TEDxUSF”
Also the paper{ “Rapamycin in ischemic stroke: Old drug, new tricks?” ] linked above, posted by member 'Guywholikessleep" mentions “lithium carbonate”.
“Rapamycin can reduce endothelial cell death and improve junctional marker expression following ischemia in vitro. mTOR-dependent (rapamycin) and mTOR-independent (lithium carbonate) autophagy inducers were used in brain microvascular endothelial cells (BMVECs) in an oxygen and glucose deprivation (OGD) model and also an MCAO model, demonstrating a beneficial effect on BBB integrity”
I would used/am considering using/adding lithium orotate.
The lithium oratate is a supplement and is absorbed better.
I am not taking high dose, Dr Thimineur is the one taking high doses. The following are quoted from his post in other forum:
"The biweekly dose is 30mg sirolimus without grapefruit juice. Every 6 week dosing of 90mg was 30mg sirolimus dosed with grapefruit juice. There are GI side effects dosing over 40-50mg at once so grapefruit juice is required to avoid these side effects when taking more than that amount. "
I have been using lithium orotate for several years now, since 2016.
“In modern medicine, lithium is used to encourage mood stability in bipolar disorder and is also being considered for the treatment of memory impairment.” Lithium study helps scientists unlock ageing puzzle - BBC News
In addition to possible mental and life extension benefits, I have found it to be a great mood stabilizer and helps with anger management, mood, etc.
It usually takes several weeks to feel any subjective effects.
This is absolutely one of my favorite supplements.
I started with 4 mg/3wk, quickly moved to 6mg/2wk, then thanks to Brandy111 I started using 4mg with GFJ. I did this for a couple months. When I learned about the life extension test I ordered 2. First test was used after 10 days because I wanted to make sure the level was low enough to switch to 10 day. Value was 1.3. I think this is low enough.
Then I tested in the morning 2 hours after taking 4+GFJ and it came up 37.6.
I am a long time user of Berberine, which interferes with cyp3a4 also.
FYI. As a physician I have negotiated pricing for sirolimus including lab draw free at LabCorp for $49.
I am hoping to monitor labs to start getting data on formulation effectiveness and dosing schedules.
Three points would give us the info we needed.
CMax. Ideally 2 to 3 hours post dose.
Mid Point: 96 hours post after CMax assessment
Trough: Approximate based on calculated half-life.
Have you guys checked your 3 or 12 hour sirolimus levels with and without grapefruit puree? This is info we all need to know. If interested, I have research pricing on sirolimus with LabCorp.
A simple method is just track a fixed power/heart rate curve. For example what is your HR at steady state 125w. Then reduce to 50W and see how long it takes for HR to reduce to 80%,
