chuck stanley An older persons Tor signal is much stronger as they grow older.  It takes much more Tor inhibition to lower it.  If the rapa has to lower Tor 1 so much there might not be enough left to affect Tor 2 for side effects.

Fred Cloud Shall do!

JH Blagosklonny has one ride at the carnival with very few paying riders: Dr. Green  (largely incoherent) and sometimes, the extremely annoying, Pete Attia; though he's as clueless as everyone else in the minefield of rapamycin.

The most important thing anyone on this forum can do is post before and after photos and extensive blood work, collate it into a spread sheet and jeep a running log. Otherwise it's just a subjective shit show.

Michael unlike you still young, old men like us are desperate and dont want to wait until FDA approves the usage and dosage after 10 years from now.

Michael  There is vastly more information in favor of rapamycin than you speak of.  Interventions Testing Program of the National Institute on Aging, Matt Kaeberlein, and even David Sinclair may be taking it as he has recently been dodging the question.  There are many, many other pieces of favorable research.  There is vastly more to the subject than just Blagosklonny being a proponent of rapamycin.

Mark Thimineur I'd just like to clarify, when you say "30mg every two weeks for about one year" am I correct in saying that you took 10mg of actual rapamycin tablets with grapefruit juice and therefore got the effect of taking 30mg of rapamycin and did that every two weeks for approximately one year?

Also, are you saying you experimented with 30mg of rapamycin tablets taken with grapefruit juice therefore giving the effect of 90mg of rapamycin all at once, at 6 week intervals and continued this for 6 months?

Mark Thimineur Thank you for posting your experience, very informative for this community.

Regarding "bloodwork", you only mentioned TC as apparently being somewhat dysregulated. But I recall Dr Green, who has a lot of patients/experience with Rapamycin, indicating that lipids, glucose dyregulation, risk of infection (thus, need for statins and/or metformin and/or antibiotics), was highly prevalent in his Rapamycin population? This experience I assume was a "proxy" marker for Rapamycin/Tor1/Tor2 impact? Thoughts vs your population? 

Does your bloodwork panel include other than lipids/glucose?

I've noticed a significant drop in my liver enzymes (GGT, ALT), improved kidney function (eGFR), much lower uric acid, with very little change in my lipids. Perhaps a slight rise in TC, but my TG/HDL and remnant cholesterol (both CVD proxies) are excellent.

Mark Thimineur I have read that higher doses of Rapa such as 20+ mg. (for the "spike" ) to get past the blood/brain barrier in order to inhibit Tor 1 in the hippocampus portion of brain where many believe ageing is controlled from.  Mark, do you know of any studies to support this theory?  I personally have used Rapa for almost 5 years, (was Dr. Green's 2nd. patient) and now take 7 mg Rapa with GFJ protocol set out by Dr. Thimineur twice a month without any side effects.  The main difference is I actually take 400 grams of GFJ juice and pulp divided into 2 doses as suggested by you.  1/2 night before and 1/2 next morning, 30 minutes before taking Rapa.  Starting weighing GFJ because of variability of size between grapefruits.  I am a healthy 75 yo male without issues.  Phenoage of 62 yo. 

MAC. I've limited sirolimus prescribing to family and friends and about 50 patients so my observations are limited. No observations of glucose elevation above normal. Definitely have seen TC elevations above norms and a tendency for decreases in RBC count to borderline levels in some patients. As a rule, most of us take metformin as well (for its own benefit) except those who experienced GI side effects on metformin.

Does any of this concern me - answer is no. Heart disease and cancer cause 700K and 600K deaths per year in U.S. (respectively) far outpacing all other disease related deaths. Benefits of sirolimus in regards to heart disease are assumed and these assumptions are strengthened by preliminary data in "The Dog Aging Project" run by Matt Kaeberlein. Similar to humans, and probably other large mammals, heart failure in dogs is a primary mortality cause. The experience of Dr. Green in which his AHC, which would have likely been fatal, going from symptomatic to asymptomatic is also notable. My current assumption is that TC elevation is a harmless SE of sirolimus. i.e. the benefits far outweighs the risk (if any) in regards to the heart. Some of us, me included, choose to treat with a small statin dose. 

Data from rodent studies are instructive for cancer as this is the primary mortality in these small mammals. Sirolimus related lifespan extension is associated with a delay in cancer among these small mammals thereby extending lifespan on average. I make the assumption that sirolimus will act as a cancer deterrent in large mammals as well. 

After "covid" and accidents, the next major causes of mortality are CVD (stroke) at 160K, pulmonary disease (150K), and Alzheimers (135K). Animal studies also provide insight that sirolimus may delay or prevent these diseases in humans and I make that assumption. If CVD and Alzheimers are combined, brain disease is the third leading cause of death and perhaps the one we all fear the most. All of the brain specific studies in rodents showed the treatment group retained a normative brain compared to controls (histological and behavioral)

In short, the deviations in RBC and TC measures are not concerning to me at this point but I try and keep an open mind.

One other issue is the innate immune system which may be affected negatively and thus make us more prone to bacterial infections. I have not seen this express itself over the past 3 years with one possible exception. A patient who had spinal hardware developed a bacterial infection and had the hardware removed. Amongst chronic pain patients many have had multiple spinal and joint surgeries and these events happen with some regularity. Was sirolimus contributory in this case - possibly - again, I keep an open mind.

Mark Thimineur I wasn't casting aspersion to the anti-aging benefits of Rapamycin, otherwise I wouldn't be taking it. As you say, wild type mice only die of cancer, and in pretty much every study on mice/Rapamycin, their lifespan is significantly increased! 

My point was very specific as to whether the "proxy" signals of your dosing interventions in your population cohort was actually "cellularly" directly connected and translatable/meaningful vs say Dr Greens cohort (far lower doses), which he seems to imply AND conclude (by way of the lipid/glucose dysregulation) is at the limit of triggering cellular dis-homeostatis. Namely, Rapamycin had gone too far, at the risk of outweighing benefits? I think that's what I am trying to learn from your amazing work...is your dosing regiment something for us (say the majority taking FAR lower doses) to learn/explore from? Do we keep upping dose until what...TC goes out of whack or other? You don't seem to have reached the same threshold as Dr Green at such high doses?

Perhaps Dr Green has a much higher baseline comorbidity population base, thus Rapamycin intervention does indeed trigger much higher metabolic side effects? I think you intimated a pro longevity (genetic predisposition AND healthy confounders?) baseline cohort in your patients, thus allowing for a much greater Rapamycin dosing tolerance?

It's too bad we don't have a readily available cellular "longevity" lab assay to individually guide in this intervention journey. There are those that question the method-type, reproducibility, and validity of DNA methylation as a definitive anti-aging proxy. 

Van Go Van!! Perhaps you meant hypothalamus? As far as I know, the hippocampus is only a short term memory associated storage region, not a master cellular homeostasis signaller.

Role of hypothalamus in aging and its underlying cellular mechanisms

https://www.sciencedirect.com/science/article/abs/pii/S0047637418300502

MAC. Thanks for correcting my typo and the cite. 

MAC. I believe Dr. Green's current weight is about 150 lbs which makes his biweekly dose about .15 mg/kg/wk which is not much different than my preferred dose of .18mg/kg/wk. My dose is based on rodent --> human dosing conversion using 42ppm rapamycin chow daily feeding  and taking into account (adusting) for even higher dose paradigms (2-3X that) and extended dosing intervals in rodent studies which seemed to decrease dyslipidemia and hyperglycemia and even improved health/lifespan. I did this work long ago and don't remember the details exactly.

I appreciate the effort to figure out optimal human dosing looking at laboratory data from ourselves but I don't believe it is possible. The rodents had far greater levels of laboratory deviation yet had extended health and lifespans which seemed to be greatest when given massive doses for a 3 month interval and then stopping. Realize that 3 months to a mouse is 10 yrs to humans. 

At this point I'm fairly comfortable dosing at this level and I believe we cannot know if we are having an effect on aging until a long time has passed. The proxies for life and healthspan (laboratory values or DNA age) are interesting but do not prove anything. At least these proxy measures are not going in the wrong direction which provides some solace.

Of note, I did not continue 90mg every 6 weeks for two main reasons. Relying on grapefruit juice to drive absorption creates uncertainty as to the exact amount my body was absorbing due to variability of GFC affect (2.5-3.5 times). The second reason was that I noticed some swings in mood and motivation which are neurotransmitter related effects. Typically these trend positive with sirolimus but too much of a good thing can produce opposite effects. 

I cannot recommend any particular dosing of sirolimus for health and lifespan extension to people who are not under my care for obvious reasons. I have my own dosing models and some observations in a limited number of people over 3 years or so along with 35 years as a practicing physician which may have some value. Sorry I can't provide better info. I try to limit comment on this topic to every couple years or so because I think it takes alot of time to observe any "anti-aging" benefit or potential problems. So far -- it seems good.

Fred Cloud you mean phenoage? That’s been proven to be 100% correlatable to human longevity/all cause mortality? Cite the studies. 

Mark Thimineur Dr. Mark. As a follow-up, have you continued regularly applying your rapa cream treatments per your original post? If so, how' s that working out?

Thanks

Michael Twice daily. Increased concentration to 6mg in 4 ounces DMSO/Aloe cream. The effects on face: I have not developed any fine wrinkles or furrowing - skin completely smooth - no crows feet, smile lines, or forehead lines. My spouse is 10 years younger and had some fine wrinkles before starting which have been gradually decreased - her skin is smoother and healthier looking. I think I have been applying for about 30 months. I made the mistake of giving it out to some friends who hound me for it when they run out. Some people just don't want to make it themselves.

Van talked to some individual who are experimenting with it internasal. They said you feel it instantly at a dose of 130ug. Takes away all brain fog immediately. You could do this in addition to your regular ROA. Want to try it?  

Van What about GFJ commercially purchased- like Tropicana ….

Al m Tropicana, no go.  Processing take necessary chemical out.  ONLY fresh grapefruit will do.  I weigh 400 grams of pulp and juice and split it from night before and 1/2 hour in morning before taking rapa. Grapefruit juice has a chemical that will block our bodies from diluting the bio-availability of rapa.  Cancer patients have been using it for years. 

Van would be too much sugar for me in the evening (200g grapefruit has about 12-15g sugar). evening spikes don't seem to play well with my sleep quality (partly supported hypothesis).

You can take it all in the morning but need to wait until lunchtime for taking rapa. That's how long it takes to decrease CYP3A4 levels (implied in the Cohen et al. 2012 paper). 

Van How can you tell if processing removes that chemical?

Chris Los I'm glad you mentioned that. Since I take an evening statin, I cant take Grapefruit in the evening.

My doc says occasional grapefruit in the morning would be okay. I gather there is a lot of variability between individuals and between grapefruits, so this is rough estimating.  I have to balance out the gfj desired effect on sirolimus and its undesired effect on my statin in late evening. I think I can get that balance by taking gfj first thing in the morning and waiting 3 - 4 hours before taking sirolimus. Similar to your schedule. 

Since I prefer ruby grapefruit and because I'm not getting full effect of the timing of the grapefruit, my guess is I will get about a 2 fold effective increase in sirolimus. 

chuck stanley You may be interested in knowing that statins are also mTOR inhibitors. You can verify this quickly with a Google search. It is why some individuals get a muscle aches from statins. 

Peter H. Howe Interesting. There might be an association with my exercise related nocturnal leg cramps. Although I take minimal dose statin, plus I do take CoQ10, it might be worth discussing a statin vacation. 

chuck stanley Chuck if you are like me you "HAVE TO" have a statin please be careful.... . I had a bypass ~30 years ago and there is nothing I can do, including veganism,  to control my cholesterol at an acceptable level.  High dose fish oil reduces my need for high dose statins by lowering triglycerides and thus my LDL-P and particle size but it is not enough.  My problem is genetics as cardiac arrest is pervasive in  several sides of my family.

Note statins also reduce your androgens and estrogens so you should monitor these. I supplement with hormone replacement therapy including pregnenolone, DHEA and testosterone and monitor through Life Extension and Lab Corp.  On the plus side statins activate the Klotho gene. Google will readily verify these statements.

Be careful and monitor.

Good luck. 

Mark Thimineur are you aware of any comparisons between the cream you make and commercially available Tacrolimus cream?

Mark Thimineur would you mind sharing the % DMSO in the cream you use?  I see a 4 oz cream with 70% DMSO/30% aloe in a cream base available online, for instance.  Thanks!

Sorry never mind, I searched the forum and found where you posted rapa cream recipe previously.

Since I'm hesitant to apply DMSO to my skin and I want the rapa to stay *in* my skin rather than be absorbed through it, I did the following:

6mg rapa dissolved in 25ml of 95% ethyl alcohol (Everclear) then gently mixed into 4oz of CeraVe lotion.  Seems to have worked beautifully.  I guess we'll see if this particular formulation actually does anything....

Mark Thimineur Any recommendation on an expiration date of the home made rapa cream? I have some from 2019. Still good to use? Thank you

Michael 

Paula Marie How does one correctly make the cream?

Paula Marie It's Mark Thimineur's formula, found here: 

https://forum.age-reversal.net/t/63j272?r=m1hq503

Mark Thimineur The innate system you touch upon is my big issue. Have their lymphocyte counts been tested?

 Resuming rapamycin after two months  to let my lymphocytes recover, a mere  3 mg of rapa [1 mg + two grapefruit fruits) caused my lymphocyte count to drop by over 35 %, to less than half of the low mark of the normal range.