Yes, this was an excellent interview. I loved the one with Ross Pelton also. Well done Krister!
4 Likes
I’ve never not heard back from him. He’s always been responsive for me for the three+ years I’ve been his patient.
I understand he’s had some health setbacks recently, so that might be part of it. Also, he had someone helping him with the admin stuff and I’m not sure if that’s the case anymore.
I’m not really defending him. I’d just suggest that if he hasn’t been responsive, it’s not because he doesn’t care about his patients.
5 Likes
I also had mild gout but that has almost of not completely disappeared. My hands have lots of issues and inflammation… to the extent that I’ve had five trigger finger surgeries and three ganglion cycles removed. But I’ve never relied on xrays for a differential for the pain which is about 70% reduced.
One other aquaintance saw his hand stiffness and pain dramatically improve though i can’t guarantee it will be your personal canary in the coal mine.
2 Likes
Do we have any data around reproductive systems and rapamycin? Any risk taking rapamycin before you finish having all your kids?
1 Like
I haven’t look much into the data of this as I have no plans to have kids. However I did read somewhere if you plan to have kids to stop taking rapamycin for a few months before trying.
Yes - we have a fair amount of data. Rapamycin has been used in organ transplant patients for over 20 years, and while they tend to be older and sicker (think obesity/diabetes etc.) many go on to have children if they are younger. Generally, you would probably want to stop taking rapamycin 6 months or so before fathering (or mothering) children. We cover the research into this here: Possible Rapamycin Risks for Healthy Humans (Part 2)
5 Likes
Thanks for the interview! Well done.
I have a question to ask him next time if you get another chance to interview him some day. In 41:33 in the video Alan said that people who are insulin resistant need a lot higher doses than those that are not insulin resistant. I would want to know his reason for thinking this. It sounds counterintuitive given that rapamycin can cause or worsen insulin resistance.
4 Likes
I’m guessing that since insulin/glucose activate mTOR, people who are insulin resistant have higher levels of mTOR activity due to higher insulin/glucose levels. Therefore, they need more mTOR suppression to bring mTOR activity to a lower level.
3 Likes
That’s a good guess. It could also work the other way around though. Since insulin can activate mTOR, being resistant to insulin can lead to insulin being less effective at activating mTOR, leading to lower mTOR levels. I guess in the end the effect depends on whether the increase in insulin levels seen in those with insulin resistance outweighs the reduced sensitivity to insulin, which isn’t easy to predict.
1 Like
Do you know if there exists any research that “being resistant to insulin can lead to insulin being less effective at activating mTOR”? Because as I have interpreting things is that generally type 2 diabetes and insulin resistance lead to higher mTOR activation. This is also one potential explaination to why these people suffer from accelerated aging. But maybe I oversimplify things here.
3 Likes
How often patients develop anemia, low ferritin level when on Rapamycin? What is the prognosis?
Is this information available in Dr.Green patients?
That’s a great question. My initial thought was that being insulin resistant will lead to lower effectiveness of insulin at activating mTOR because that’s kind of included in the phrase “insulin resistance”. In other words, being insulin resistant generally means that your cells do not respond to insulin as effectively so you need more insulin to do the things insulin normally does. This means that anything activated by insulin would be activated less by the same level of blood insulin in someone that’s insulin resistant compared to someone that’s not.
However. Thinking about this a bit more deeply I realize that it’s not that simple. The insulin resistance could effect different things differently. Consider this. Insulin is found in the blood and to have effects on cells it needs to bind to insulin receptors on the surface of the cells. That initiates a cascade where various intracellular proteins and kinases are sequentially activated and some inhibited. Some of the intracellular processes lead to increased glucose uptake. Others lead to activation of mTOR or other things. You could have significant inhibition of the processes that lead to increased glucose uptake while having no inhibition or even an increase in some other processes. This would still mostly be detected as insulin resistance, since you would experience elevated blood glucose and insulin, which are the markers people use to detect insulin resistance. However that doesn’t necessarily mean the other insulin responsive processes are similarly inhibited. Overall, I would expect activation of various other things like mTOR being weaker in states of insulin resistance if insulin levels are the same. But again, this might not be the case. Also, on the other hand, during insulin resistance, the body will need to produce more insulin to compensate for the resistance. The higher level of insulin in the blood might as well make up for the lack of stimulation of the intracellular processes that resulted from the low sensitivity to insulin.
Overall this is very complicated, and I’m not aware of any studies that give us good answers here (not that I have looked into it a lot or anything). It’s also quit elikley that insulin resistance has different effects on mTORC1 than on mTORC2. When I asked ChatGPT it said that insulin resistance might activate mTORC1 but impair mTORC2. If that’s true then one would probably tolerate rapamycin best if one is insulin sensitive. That’s actually in line with what Alan said in your interview. He said people that are lean tolerate it better and have better results than those that are obese and insulin resistant. Note thought that we can’t trust ChatGPT here. It sometimes says some bullshit. Maybe someone is willing to dig into studies on the effects of insulin resistance on mTOR activation to find out what the likely effect is to be.
1 Like
I don’t know how you could confuse the effects of insulin on glucose transport with the effects of insulin on mTOR.
To me it seems very logical that higher plasma insulin level would result in greater mTOR activation.
2 Likes
I’m not confusing the effects of insulin on glucose transport and on mTOR. I’m making predictions based on the fact that the pathways are related!
Yes but the increase will be reduced if you’re less sensitive to insulin. Being insulin resistant your cells don’t sense the insulin well and they’re not going to activate mTOR much because insulin is high if they don’t see the insulin because you’re resistant to it.
Insulin signaling is a complicated process involving activation of several steps. As a simplification, when insulin binds to the insulin receptor on the surface of cells it leads to activation of IRS then PI3K then Akt. Akt then influences both glucose uptake and mTOR activation. Insulin resistance can often occur at the level of IRS, PI3K or Akt and if the activation of any of these decreases due to reduced sensitivity to insulin, the result should be not only reduced activation of GLUT-4 (leading to impaired glucose metabolism) but also reduced activation of mTOR. There are many different ways to be insulin resistant, but given the pathways, reduced sensitivity to insulin is quite likely to also lead to reduced sensitivity to mTOR activation.
2 Likes
It is a positive feedback loop:
Insulin resistance leads to increased mTOR activity and increased mTOR activity in turn leads to more insulin resistance.
No wonder diabetics age faster than those with controlled plasma glucose levels.
2 Likes
Where is the positive feedback loop? Increased mTOR activation results in reduced sensitivity to insulin but it makes no sense that insulin resistance leads to higher mTOR activation. mTOR is activated downstream of insulin so less insulin signaling will generally lead to reduced mTOR activation. If you think otherwise you’re going to have to provide reasoning or evidence for that claim.
I’ve had the same response lately. I have had a cold for the last 3 weeks. It’s been 5 years ago since I had a cold. I haven’t stop Rapamycin while going through this. I am going to take a couple of weeks off now to help with recovery. I’m sitting in dr office now.
1 Like
I do worry what we’re doing to our immune systems. There was an interview with a doctor (who runs a rapamycin clinic) posted on here a couple of weeks ago, in which he said it reduces our immunity to bacterial (but not viral) infection, adding confusingly that we should take antibiotics as soon as we feel a cold coming on - made no sense - I asked for clarification but as yet there has been none
2 Likes
Yes, why would anybody get an antibiotic for a cold? I know that quick care and emergency rooms typically will prescribe antibiotics just to satisfy their patients.
I don’t know how many times over the years I have heard people say “Yeah, I got the flu and had to go to the doctor to get an antibiotic”.
Other than placating a patient is there some other reason I don’t know about?
If you are sick from a cold why don’t you stop taking an immune suppressant while having it?
No way it’s worth it to take it then. Plenty of non-sick weeks of the year.
4 Likes