Much needed article. I have ruminated for a long time based on my reading that, while living with mTOR permanently active leads to modern lifestyle diseases, being permanently under the influence of AMPK is undesirable and equally a mistake, a point well made in Mattson’s paper on neuroplasticity. I’m so glad to see this confirmed in black and white in another great post from you.
Thank you for a very informative article. Like many I have also been grappling with the paradox of growth vs mtor inhibition.
Your nuanced recommendation of targeted short period cycling is spot on. You really need to think what youare taking rapamycin for, to what end and howlong. Longevity itself is too vague and unhelpful in the context of rapamycin.
I took it for 9 months; weekly 6mg, then tapered off to 3mg towards the end to modulate my immune system hit by 20 years on methotrexate for influenza vaccine induced autoimmune myocarditis. I did intermittent fasting and low calorie intake for 3 days after dosing. My rheumatologist had recently recommended increasing methotrexate as I was no longer responding with creeping crp and fevers. It worked a treat! I have stopped rapamycin a year ago and methotrexate 2 years ago. Autoimmune gone! I assume my treg's got boosted as in the small paper on rheumatoid arthritis patients from couple of years ago. I am 56 now. Would I take it if I was well? No. But then again everyone over 50 have some sort of chronic disease related to inflammation that could benefit from intelligent immune suppression like mine albeit with few worrying skin infections under doctors supervision.
I think people are jumping the gun into pharma on this, and I think pharma is incapable of a sensible approach, since the sensible approach is to give the immune system the tools it needs to regulate itself, not to try to turn it up or turn it down. Pharma is riddled with intrinsic tradeoffs on this approach. Glad your issue settled out though.
After the death of M.V. Blagosklonny at the age of 67 from metastatic lung cancer (this is public information), rapalogs will be assessed not as geroprotectors or oncoprotectors, but as immunosuppressors, which is what they are. The oldest scientific school of Soviet gerontology has been talking about this for a long time.
Thank you for a very informative article. Like many I have also been grappling with the paradox of growth vs mtor inhibition.
Your nuanced recommendation of targeted short period cycling is spot on. You really need to think what youare taking rapamycin for, to what end and howlong. Longevity itself is too vague and unhelpful in the context of rapamycin.
I took it for 9 months; weekly 6mg, then tapered off to 3mg towards the end to modulate my immune system hit by 20 years on methotrexate for influenza vaccine induced autoimmune myocarditis. I did intermittent fasting and low calorie intake for 3 days after dosing. My rheumatologist had recently recommended increasing methotrexate as I was no longer responding with creeping crp and fevers. It worked a treat! I have stopped rapamycin a year ago and methotrexate 2 years ago. Autoimmune gone! I assume my treg's got boosted as in the small paper on rheumatoid arthritis patients from couple of years ago. I am 56 now. Would I take it if I was well? No. But then again everyone over 50 have some sort of chronic disease related to inflammation that could benefit from intelligent immune suppression like mine albeit with few worrying skin infections under doctors supervision.
The Ray Peat/Mercola crowd would not agree with this. They would agree with not perpetually lowering mTOR, but not with fasting and stimulating autophagy like this. Their first qualm would be that this raises stress hormones (e.g. cortisol, adrenaline, glucagon) and that is not good and is too much of a cost. They would also say that being in a fed state signally abundance all the time is optimal. Im not sure if I agree with this.
I would love to get your opinion chris about their arguments and what you think about the bioenergetic view of health, which basically centers around optimizing ATP production and minimizing oxidative and reductive stress.
Chris I really wonder if you looked at this issue in depth enough. Matt Kaeberlein posted a rebuttal to your points that appears to be more consistent with what the science actually says. It appears that you cherry picked all the negatives. You can see Matt's rebuttal here: https://youtu.be/WJNHqM8kxqI?si=xF9aXbjXV-Lw9PDm
Sir, I think you have the pharmacokinetic conversions wrong. Or to put it differently, you have ignored the vastly speedier pharmacokinetics of rapa in mice as compared to humans when comparing frequency of dosing. This isn't my analysis, but I believe it to be correct.
""The equivalent of daily rapamycin in mice is NOT daily rapamycin in humans.
This is because mice metabolize rapamycin 10 times faster than humans.
The equivalent of daily rapamycin in mice is actually taking rapamycin every 7-14 days or so.
The half life of rapamycin in mice is around 6.4 hours. The half life in humans is around 62 hours. This means that a human taking rapamycin every 10 days is mimicking a mouse taking it every day. This is where the rationale for a 7-14 day cycle in humans comes from.
If a human were to take rapamycin every single day, this would be the equivalent of giving a mouse rapamycin every 2.4 hours. This is not a dosing schedule that has ever been shown to extend lifespan in mice, and it may have negative consequences for the animals.
A human taking rapamycin every 10 days or so is NOT ”pulsing” or “cycling” the rapamycin any more so than a mouse taking it every day. They are more or less equivalent. The cycle between mice and humans is basically the same in this case.
Mice on daily rapamycin have mTOR suppressed for most of the day. Humans on weekly rapamycin have mTOR suppressed for most of the week. The area under the curves is basically the same in both cases."
If that is correct, then all of your comparisons of human daily dosing to mouse daily dosing are not accurate. Rather, human dosing every 7 - 14 days is comparable to mouse daily dosing.
Chris I really wonder if you looked at this issue in depth enough. Matt Kaeberlein posted a rebuttal to your points that appears to be more consistent with what the science actually says. It appears that you cherry picked all the negatives. You can see Matt's rebuttal here: https://youtu.be/WJNHqM8kxqI?si=xF9aXbjXV-Lw9PDm
Chris I really wonder if you looked at this issue in depth enough. Matt Kaeberlein posted a rebuttal to your points that appears to be more consistent with what the science actually says. It appears that you cherry picked all the negatives. You can see Matt's rebuttal here: https://youtu.be/WJNHqM8kxqI?si=xF9aXbjXV-Lw9PDm
Thanks for the thoughtful post. I also saw that Bryan Johnsen discontinued Rapamycin due to negative effects. So its one substance I will not experiment with :) thanks
Extrapolating results from mice to humans is highly uncertain. Even among rodents - comparing hamsters and rats - results can differ by orders of magnitude ( 1 vs 1000) for different pollutants.
I have been working on a mitochondrial analog in the area of astrophysics and would appreciate another set of nutrition focused, biochemist, eyes on it. Would you be interested in seeing some draft works? I have a mechanism of action or chemical analog ETC worked out. Too many details for a text box....your biochemistry skills would be useful as a peer reviewer or collaborator of the theory.
Agree. Haven’t seen this laid out before. Reminds of all of the issues of VEGF inhibitors- as angiogenesis (VEGF) and muscle protein synthesis (mTORC) are essential for the healthspan benefits associated with exercise
Much needed article. I have ruminated for a long time based on my reading that, while living with mTOR permanently active leads to modern lifestyle diseases, being permanently under the influence of AMPK is undesirable and equally a mistake, a point well made in Mattson’s paper on neuroplasticity. I’m so glad to see this confirmed in black and white in another great post from you.
Excellent write up. Could you do a deep dive on Spermidine please?
Thank you for a very informative article. Like many I have also been grappling with the paradox of growth vs mtor inhibition.
Your nuanced recommendation of targeted short period cycling is spot on. You really need to think what youare taking rapamycin for, to what end and howlong. Longevity itself is too vague and unhelpful in the context of rapamycin.
I took it for 9 months; weekly 6mg, then tapered off to 3mg towards the end to modulate my immune system hit by 20 years on methotrexate for influenza vaccine induced autoimmune myocarditis. I did intermittent fasting and low calorie intake for 3 days after dosing. My rheumatologist had recently recommended increasing methotrexate as I was no longer responding with creeping crp and fevers. It worked a treat! I have stopped rapamycin a year ago and methotrexate 2 years ago. Autoimmune gone! I assume my treg's got boosted as in the small paper on rheumatoid arthritis patients from couple of years ago. I am 56 now. Would I take it if I was well? No. But then again everyone over 50 have some sort of chronic disease related to inflammation that could benefit from intelligent immune suppression like mine albeit with few worrying skin infections under doctors supervision.
I think people are jumping the gun into pharma on this, and I think pharma is incapable of a sensible approach, since the sensible approach is to give the immune system the tools it needs to regulate itself, not to try to turn it up or turn it down. Pharma is riddled with intrinsic tradeoffs on this approach. Glad your issue settled out though.
After the death of M.V. Blagosklonny at the age of 67 from metastatic lung cancer (this is public information), rapalogs will be assessed not as geroprotectors or oncoprotectors, but as immunosuppressors, which is what they are. The oldest scientific school of Soviet gerontology has been talking about this for a long time.
Thank you for a very informative article. Like many I have also been grappling with the paradox of growth vs mtor inhibition.
Your nuanced recommendation of targeted short period cycling is spot on. You really need to think what youare taking rapamycin for, to what end and howlong. Longevity itself is too vague and unhelpful in the context of rapamycin.
I took it for 9 months; weekly 6mg, then tapered off to 3mg towards the end to modulate my immune system hit by 20 years on methotrexate for influenza vaccine induced autoimmune myocarditis. I did intermittent fasting and low calorie intake for 3 days after dosing. My rheumatologist had recently recommended increasing methotrexate as I was no longer responding with creeping crp and fevers. It worked a treat! I have stopped rapamycin a year ago and methotrexate 2 years ago. Autoimmune gone! I assume my treg's got boosted as in the small paper on rheumatoid arthritis patients from couple of years ago. I am 56 now. Would I take it if I was well? No. But then again everyone over 50 have some sort of chronic disease related to inflammation that could benefit from intelligent immune suppression like mine albeit with few worrying skin infections under doctors supervision.
The Ray Peat/Mercola crowd would not agree with this. They would agree with not perpetually lowering mTOR, but not with fasting and stimulating autophagy like this. Their first qualm would be that this raises stress hormones (e.g. cortisol, adrenaline, glucagon) and that is not good and is too much of a cost. They would also say that being in a fed state signally abundance all the time is optimal. Im not sure if I agree with this.
I would love to get your opinion chris about their arguments and what you think about the bioenergetic view of health, which basically centers around optimizing ATP production and minimizing oxidative and reductive stress.
And thanks for a great article!
Chris I really wonder if you looked at this issue in depth enough. Matt Kaeberlein posted a rebuttal to your points that appears to be more consistent with what the science actually says. It appears that you cherry picked all the negatives. You can see Matt's rebuttal here: https://youtu.be/WJNHqM8kxqI?si=xF9aXbjXV-Lw9PDm
Sir, I think you have the pharmacokinetic conversions wrong. Or to put it differently, you have ignored the vastly speedier pharmacokinetics of rapa in mice as compared to humans when comparing frequency of dosing. This isn't my analysis, but I believe it to be correct.
""The equivalent of daily rapamycin in mice is NOT daily rapamycin in humans.
This is because mice metabolize rapamycin 10 times faster than humans.
The equivalent of daily rapamycin in mice is actually taking rapamycin every 7-14 days or so.
The half life of rapamycin in mice is around 6.4 hours. The half life in humans is around 62 hours. This means that a human taking rapamycin every 10 days is mimicking a mouse taking it every day. This is where the rationale for a 7-14 day cycle in humans comes from.
If a human were to take rapamycin every single day, this would be the equivalent of giving a mouse rapamycin every 2.4 hours. This is not a dosing schedule that has ever been shown to extend lifespan in mice, and it may have negative consequences for the animals.
A human taking rapamycin every 10 days or so is NOT ”pulsing” or “cycling” the rapamycin any more so than a mouse taking it every day. They are more or less equivalent. The cycle between mice and humans is basically the same in this case.
Mice on daily rapamycin have mTOR suppressed for most of the day. Humans on weekly rapamycin have mTOR suppressed for most of the week. The area under the curves is basically the same in both cases."
If that is correct, then all of your comparisons of human daily dosing to mouse daily dosing are not accurate. Rather, human dosing every 7 - 14 days is comparable to mouse daily dosing.
Researchers doubled the normal lifespan of mice just by giving them activated charcoal powder.
Chris I really wonder if you looked at this issue in depth enough. Matt Kaeberlein posted a rebuttal to your points that appears to be more consistent with what the science actually says. It appears that you cherry picked all the negatives. You can see Matt's rebuttal here: https://youtu.be/WJNHqM8kxqI?si=xF9aXbjXV-Lw9PDm
Chris I really wonder if you looked at this issue in depth enough. Matt Kaeberlein posted a rebuttal to your points that appears to be more consistent with what the science actually says. It appears that you cherry picked all the negatives. You can see Matt's rebuttal here: https://youtu.be/WJNHqM8kxqI?si=xF9aXbjXV-Lw9PDm
Thanks for the thoughtful post. I also saw that Bryan Johnsen discontinued Rapamycin due to negative effects. So its one substance I will not experiment with :) thanks
Extrapolating results from mice to humans is highly uncertain. Even among rodents - comparing hamsters and rats - results can differ by orders of magnitude ( 1 vs 1000) for different pollutants.
I have been working on a mitochondrial analog in the area of astrophysics and would appreciate another set of nutrition focused, biochemist, eyes on it. Would you be interested in seeing some draft works? I have a mechanism of action or chemical analog ETC worked out. Too many details for a text box....your biochemistry skills would be useful as a peer reviewer or collaborator of the theory.
Agree. Haven’t seen this laid out before. Reminds of all of the issues of VEGF inhibitors- as angiogenesis (VEGF) and muscle protein synthesis (mTORC) are essential for the healthspan benefits associated with exercise
@Chris Masterjohn, PhD is this your company?
Mito.me
Asking as it’s got your name on it, but you haven’t shared anything about it on social media or Substack