#61

AIUI and I have not checked the references, mTORC2 inhibition comes in after a period of inhibiting mTORC1. Hence if you keep the lower thresholds sufficiently low between doses either
a) You won’t inhibit mTORC2 or
b) You will only temporarily inhibit it.

It strikes me it may be a measure of a greater shortage of nutrients than mTORC1.

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#62

SGLT2 inhibitors are expensive in the US. What about remogliflozin out of India as 100mg BID? It showed essentially a 20mg/dl and 40mg/dl drop in blood glucose in fasting and postprandial states respectively. Released in 2019 in India. Any experience with it?

#63

You can buy empagliflozin Jardiance from India and have it shipped to the USA. That’s what I do.

1 Like
#64

Good to know. I am discouraged by the ~10mg/dl rise in my fasting glucose on just 1mg weekly of rapamycin (and not happy with my fasting glucose before rapamycin, to be honest). Regarding my BS, the thought, “It doesn’t seem fair” has crossed my mind since I climb 4500 up steps (and 4500 down) each morning, have a healthy 22.8 BMI, and work hard at keeping my carb intake really low-- I stress over 2 gm added sugar! Thank you for the info. By the way, I had a pt some years ago with Fournier’s gangrene, not on an SGLT2 inhibitor, and that is a nasty disease.

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#65

BMI is not a reliable marker of healthy body composition. If you really want to know, get a Dexa body comp scan to see how much and where you have body fat stored. I am 16.3% body fat but have too much visceral fat. My BMI is 26.8.

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#66

I think reasonable people can disagree with this. Obviously we don’t have good dose/response information on rapamycin in healthy humans with regard to longevity. But I suspect we may never get this, given the problems with funding such studies and the timescales involved. So then the issue becomes “how much do we know, in what organisms, and can we may educated guesses from that data and then cautiously (with a lot of testing and monitoring) work towards acting on the best knowledge we have?”.

I would posit that some people may want to take this approach, depending on your personal risk profile, and access to testing facilities, etc.

Its not like we have zero data on this.

  • We know the dose response profile of rapamycin in longevity in mice from the many ITP and other studies on this (see below).
  • We have some early data from the marmoset study with approximately the equivalent to the mouse studies of 14PPM, which equates (by Adam Salmon’s estimate) to around 30mg per day (or perhaps every two days - need clarification from Adam on this, given the approx. 24 hour half-life for rapamycin in marmosets) for a typical 60kg human. This seems to be providing close to the mouse longevity benefit of 10% to 15% healthy lifespan improvement.
  • If we see the same dose response for healthy longevity in mice and marmosets (e.g. 14ppm translates into a healthy lifespan benefit of around 10% to 15%, it seems that there is a reasonable chance it would also translate to humans, all things being equal).
  • And, I think we may be able to measure the “failure of the dosing regiment”, by doing frequent and regular blood testing to track key variables. If they get too far out of wack, I would just the dosing level a failure. See this related thread: Ideas on Protocols for Testing Higher Rapamycin Doses

Assuming a starting level of 6mg dosing once per week, it seems like it might be feasible to slowly increase that dosing level safetly by regularly monitoring all the key blood measures that might indicate negative side effects, like LDL, APOB, blood sugar and insulin levels, and markers of immune suppression, like white blood cell levels, TREGs, etc.

I suspect that as you increase your dose past 6mg once per week that the risks increase and so more and more care is required as you increase the dose. But it does seem conceivable that a protocol could be developed to balance the risk and potential reward, at an individual level. I’m not advocating this for anyone, it just seems that there is a potential pathway forward in this area with an approach that controls the risk.

Here is the mouse dose/response data we have:

I think daily dosing in mice is roughly equivalent to about once every 4 days or so in human terms given the speed that mice metabolize rapamycin is about 4 times faster.

Sirolimus
Dose		 Mouse
mg/kg/day
Dose		 Mouse:
Blood/Sirolimus
Level		 Human
mg/kg/day
Dose		 Dose for 60kg Human Daily Dose adjusted for longer half-life (/4)
4.7ppm ∼2.24 3 to 4 ng/mL 0.182 mg/kg 10.92 mg 2.73 mg
14ppm ~6.67 9-16 ng/mL 0.542 mg/kg 32.54 mg 8.135 mg
42ppm ~20 23-80 ng/mL 1.626 mg/kg 97.56 mg 24.39 mg
126ppm ~60 4.878 mg/kg 292.68 mg 73.17 mg
378ppm ~180 45 to 1800 ng/mL 14.634 mg/kg 878.04 mg 218 mg
Sirolimus
Dose		 mg/kg/day
Dose		 Blood/Sirolimus
Level		 Male Median LS Increase Female Median LS Increase
4.7ppm ∼2.24 3 to 4 ng/mL 3% 16%
14ppm ~6.67 9-16 ng/mL 13% 21%
42ppm ~20 23-80 ng/mL 23% 26%

Based on the FDA animal to human dosing conversion guide here.

Note: ½ life for sirolimus in mice is approx. 15 hours, vs. approx. 62 hours in humans. So, mice metabolize sirolimus approximately 4 times faster than humans.

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#67

All the information you’re providing is excellent, but it’s not based on human trials and it doesn’t address the goal of delaying aging.

We simply don’t know whether more rapamycin is better for anti-aging.

It may be that more is worse.

Whether or not humans can tolerate a higher dose is not the point. We need to know whether more will result in a longer lifespan.

For example, there have been studies on the impacts of aerobic exercise on aging.

Analysis of runners has shown that the benefits of running plateau after 30 to 45 minutes of running.

People who run marathon distances regularly die younger than people who run 10K.

The effects of running on MTor are not dissimilar to the effects of rapamycin, so it’s entirely possible we’d see a similar result, if human trials were done on rapamycin.

I acknowledge that human trials aren’t practical, as they would take decades. But humans are not mice.

We’re only a couple of years away from data from the dog aging project. While that project won’t address dosing, it will hopefully confirm if the anti-aging effect in larger mammals mirrors what we’ve seen in mice.

Assuming dogs perform as well as mice, we may have a little more comfort in using mouse data to predict outcomes in humans.

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#68

I would argue that the mouse and marmoset longevity data do address the goal of aging; as those are all based on rigorous academic studies on longevity with rapamycin across multiple species, getting closer and closer genetically to humans. Is it perfect? No, but I think its relevant data that allows us to make a reasonable hypothesis that increasing from our current dosing (say 6mg per week for a 60kg person, or about 0.1 mg/kg once per week) to a higher dose; perhaps 0.25 mg/kg once a week or more often, is likely to increase healthy lifespan if (and this is a big “if” right now), you can keep side effects at a low level). Obviously not a bet everyone would want to make nor could they without the proper medical / testing support. But not an unreasonable bet from my perspective.

While I love the dog aging study, and all the effort going into it, I anticipate that there will be a few issues with it. First of all they had their funding cancelled by the NIA/NIH this year, so its up in the air whether it will ever get completed. I hope so, but I’ve not heard of their funding status for some time now.

The second issue is that the dosing level in the dogs is very low (compared to the marmosets); only 0.15mg/kg, and that translates to a very low dose in mice, probably less than the 4.7 ppm the ITP has tried (perhaps someone with some time can do the calculations), which resulted in only a 3% median male lifespan increase. The Dog aging study is only powered enough to detect a 10% lifespan increase in the dogs currently (going from memory here), so if its as effective in dogs as mice, the study will not be able to come to any conclusions. More info on the dog aging study here: How Do I Get Rapamycin for My Dog?

So, I think the best data we will have for rapamycin over the next 5 years will most likely be the marmoset data. Adam Salmon says they are working on a number of papers on the marmoset longevity study, so I really look forward to the information these papers provide.

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#69

Sheesh I’m near 71, female, 140pounds and started it to see if it helps my chronic fatigue. Everything I read before starting it said typical dose is 6mg/week so that’s what I’ve done the past 4 weeks. (Built up to that for 6 weeks.). Now I’m thinking that’s way too much, but I haven’t had any side effects, but haven’t had blood drawn. How soon should one have blood drawn? If it’s ok and no other side effects do you think I should stick with 6 or go to every 2 weeks?

#70

Noneyah: We simply don’t know whether more rapamycin is better for anti-aging.
It may be that more is worse.

And that’s where I’m gonna agree with you bud. Because I just got my GlyanAge test back on inflammation. At higher doses for 7 months…
my inflammation in my body was higher, and we know that’s a killer age 51 years. On a lower dose 6 to 12 mg. My inflammation rates were at the age of about 42 to 44. Years.

Big difference.

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#71

Hi Candleflower,

Hi, and welcome to the forums. We’ve had some people here relate their use of rapamycin for CFS. You can see some of these discussions at the links below. The use of rapamycin in treatment of CFS is a new application that very few of us have experience with here. I don’t think I can provide much guidance. The key issue (if you have no bothersome side effects right now) is that rapamycin can increase lipid and blood glucose levels, and while in the short term these are not an issue typically, they can become issues long-term. So I would advise testing and checking these every month or two and work with your doctor on how best to address them if you see any changes that are worrisome:

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#72

I would stick with the 6 mg every week as long as you don’t have side effects, but would check blood values soon.
I am a female, 58 years, 127 pounds taking 5mg + GF every week without any side effects and my recent bloodwork was just fine (fasting glucose + lipids) I take Metformin 3-4 times a week depending on exercise levels and 5 mg of Rosuvastatin.
There might be a different side effect profile between males and females,only anecdotally I see less side effects in my female patients.

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#73

This discussion, and some other threads moving along in parallel (Marmoset results) are missing a major unknown and likely confounder when trying to estimate human dosing based on animal studies - We don’t know if the therapeutic, optimal anti-aging serum or interstitial concentrations in human are the same as they are in model organisms. It seems very likely that they are not, and that they could be much lower than those observed in small-bodied, (relatively) short-lived organisms like mice and marmosets.

Mice, for example, are incredibly robust animals, with a physiology geared sharply towards growth and repair. They live for a short period of time and produce copious litters. They can repair damaged tissues incredibly quickly and efficiently. In animal research, they undergo surgery in nonsterile conditions and recover without issue due to their incredibly strong immune systems. They heal their surgical wounds orders of magnitude more quickly than humans. They can regrow amputated digits. They exhibit adult neurogenesis while humans most likely do not. Their cells grow more quickly and migrate faster in a dish. This list could go on and on, but the key point is that mice are geared towards much faster growth and more cell division. This is likely driven by increased tone in many pathways, including mTOR. Inhibiting this growth program (to achieve longevity benefits from autophagy, etc.) is likely to require more inhibition (i.e., higher circulating rapa) in mice than in humans.

The animal dosing conversions discussed here and elsewhere account for differences in pharmacokinetics, but not for differences in therapeutic drug concentrations. I haven’t seen any publications that address this, but it could be studied with cell models.

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#74

[quote=“Agetron, post:70, topic:14562”]
We simply don’t know whether more rapamycin is better for anti-aging.
It may be that more is worse.

Show me any mammal studies that show more is worse. This is contrary to Dr. B’s thoughts and contrary to the mouse studies that I have read.

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#75

You can apply this to so many things in this forum :slight_smile:

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#76

Hahaha old timer… :wink: I certainly understand Mikhail Blagosklonny, who was going high because he had existing cancer. But I believe for the normal person that would not be the route to take. The same with mice. Shorter life higher metabolism. We are not mice.

I’m basing this on my personal research. I’m human. My N=1 in which my glycans on my proteins, which are very measurable for inflammation, shot out of control only during 7 months of high rapamycin dosing… during an almost 4 year period all was low equally, it shot up my inflammation – 14 years, Same with my TruMe methylation. Two unrelated biological markers Show the correlation related to rapamycin high dose… like it or not. I see myself as pretty genetically normal. So those increases to me were a red alert.

Then, when I reduced back down to 6 to 8 mg rapamycin over an 8 month period. Those numbers went back to lower inflammation.

I just visited with Alexander Vojta about my numbers over the past 3 years. He confirmed my test scores. I’m 22 years younger, than my chronological age. He said, I’m in a very small fraction of all the tens of thousand people that they measure with this age discrepancy, I am unique to them all. My difference from them. I’m the only one on rapamycin as an early adopter.

My glycans show me to be a complete abnormality in their system.

Go ahead and take more, but I think I am one of the few on here who consistently measures my biomarkers since starting rapamycin and have the dose patterns. It’s not been cheap.

I will be putting out a total review of my 4 years, images, charts… blood panels, biomarkers and people can do what they want with the information.

For what it’s worth, Alex Vojta concurs with me. A lower amount of rapamycin 4-6 mg seems to be the better route to go.

After discussing it with Alex… I’m actually going to drop down to 4 mg rapamycin weekly. For the next 6 months, no grape fruit juice. And see what my biomarkers are with both GlyanAge and TruMe.

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#77

@Agetron Do you think that perhaps a lot of the benefits you are seeing now were gained when you were taking high doses of Rapamycin? If you did a high dose for 7 months and then returned to a lower dose, were your results better than before you did the higher dose?

Yes, inflammation and side effects will probably shoot up while you are high-dosing. That’s why it’s probably best to do this for a short period (2 years?) and then switch to a lower dose. Doing this when you are younger (30-50 years old) is probably best. Based on the mouse studies, I think a short-term period of high dosing may convey permanent benefits.

Right now we don’t have definite answers and can only go off of what has worked for mice and marmosets. I don’t see any long-term health detriments to taking high-dose Rapamycin for a couple of years as long as the side effects are controlled as well (mainly hyperlipidemia and hyperglycemia).

Who knows, maybe chronic low doses will be good enough for the majority of the longevity benefit? But, for me, I’m going to try high doses for a while and then keep a close eye on my blood work.

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#78

@DeStrider @Agetron Its a question I’ve been wondering about. If you measure the effect of exercise on the body while exercising, it might not look very healthy. Yet, with consistent exercise and sufficient recovery, exercise is very healthy. It’s a challenge to know how to interpret the effect during ther period of stress. But caution is warranted. The chance of doing damage must be higher than the chance of stumbling upon an unknown pathway to life and healthspan extension.

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#79

I would add also to major differences with other animals and primates, because we cook our food, how humans digest food and the efficiency of the process makes our physiology very different than any lab animal. Using animal studies to divine human dosing schedules is likely fundamentally flawed.

Chimpanzees chew their food for four to six hours a day, while humans spend barely an hour doing so. In comparison with non-human primates, we have smaller oral cavities, jaws and teeth, and weaker chewing muscles. Even our digestive system is, proportionally, shorter, and therefore less efficient.

Humans’ physiological investment in digestion is also lower than expected: we spend between six and seven percent of our energy on it, compared with the average 13% to 16% among other mammals. We use much more energy and we have fewer biological resources to obtain it. How can we explain this paradox? We are ‘cooknivores’: How cooking forever changed our digestive systems | Society | EL PAÍS English

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#80

Chris wrote: You did a high dose for 7 months and then returned to a lower dose, were your results better than before you did the higher dose?

Going back to a lower dose the results went back closer to lower… but were not better. Like a cleanse and later better. Nooe.

I’ve lost about 2 years. Which what are 2 years of life worth in today’s market? I still having a 22 years age difference between my chronological and biological age. I’m not moaning and groaning. However, it was better before the higher dose. Now on the lower dose and even going to go a bit lower. Pure rapamycin 4 mg no GFJ. I will retest in 6 months.

I will be curious to see if I can pick back up those two years I lost.

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