It’s exactly what you said though. Ignore LDL because it increases because of mTOR inhibition and figure out if that’s bad.
It’s called ignoring LDL.
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Right now my markers are okay, below the limits of pre-type II diabetes even with rapamycin, so I am not worried about it enough to pursue it.
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Hardly. Mtorc2 impacts numerous metabolic processes. It would be narrow minded to simply say that Rapa increases LDL, so we’ll take a statin and all is good. IMO, we should look at an elevated LDL as a marker of mtorc2 synthesis inhibition and decide whether that is important. Now, I may be wrong, maybe LDL elevation is related to mtorc1 inhibition?
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No it is not important at all. You increase LDL you will increase your risk of heart disease.
Or I don’t even know what you’re talking about.
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Here is a good paper on MTOR inhibition on lipids and glucose. MTORi dosages usually started at 5 or 10 mg daily (for everolimus).
mTOR inhibitors are known to induce dyslipidemia in 25–76% and hyperglycemia in 13–50% of patients [8–10].
In the EXIST trials (follow-up up to 5 years), the phase III trials that led to approval of mTOR inhibition in TSC patients, dyslipidemia was reported in 5–30%, but no new cases of diabetes were reported [3, 4, 6]. In a small prospective study among mainly children with TSC using mTOR inhibition, dyslipidemia and hyperglycemia were reported in 72% and 22% of children, respectively, but the highest fasting glucose did not reach diabetic levels (108 mg/dl (6 mmol/l)) [11].
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Perhaps. But what would be your next step on this.
I’m going to review what Dudley Lamming has been writing on the topic : Evidence that mTORC2 inhibition is detrimental, by Dudley Lamming
And here: New Paper: Targeting the Biology of Aging with mTOR inhibitors
I’m all for learning more about mTORC2, and getting other researcher’s opinions (one of the issues is that it seems most of the negative mTORC2 inhibition information is coming out of Dudey’s lab, and from Joan Mannick, both of whom have a horse in the race with their own mTOR inhibition drugs and startup companies… so being skeptical is entirely reasonable in this case.
But, what next?
I think, given the known risks of LDL/ lipid disregulation, my bias will be to treat it and try to keep it low.
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Somehow it’s all starting to make sense to me. Why there isn’t a mTOR inhibitor pushed by big pharma to treat age related diseases. The increase in LDL is super serious. All of the big pharma guys sees it. I’m sure there has been conversations about this in closed doors with 140 IQ pharma researchers. And people like Matt isn’t in on it. He seems like he’s rebelling and seeing potential which big pharma somehow ignored. This as I read about the rate of hypercholestroemia and potential mechanisms.
Most important development needs to be a mTOR inhibitor that doesn’t increase LDL by such an amount. Rapamycin is ancient technology, and very rough, requires countermeasures to counteract the negative LDL increase.
Pharma guys want things that decrease LDL. Increasing it in a study would increase cardiovascular events if it it had enough statistical power, is the expectation. No one is going to study it because of that.
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Also from the above paper.
Non-HDL-c has shown to be the most strongly associated with cardiovascular risk, with a trend in increased risk of 1.16 for an increase of 0.9 mmol/L [24]. In our population the median non-HDL-c increased from 3.5 to 3.9 mmol/L. Our results suggest that the effect is not temporary. Furthermore, mTORi therapy is expected to be used in younger age and treatment is usually long—term. Because lifelong mTORi therapy is frequently indicated, start of lipid lowering medication should be considered in the first year of treatment if hypercholesterolemia occurs. At the same time, if cholesterol is not elevated after 1 year of treatment, our data supports to stop regular cholesterol testing and only do so by indication.
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I also read that study and checked out the papers they cited on mechanisms, but the two different papers on why mTOR inhibition increase apoB were contradicting each other. Now I am looking into the effect on PCSK9, someone has talked about that on here earlier. PCSK9 is basically a way for the body to keep as much cholesterol as possible…useful in the past in times of starvation, etc. Which makes me wonder if caloric restriction effect on mTOR is one of the mechanisms the body uses to keep as much cholesterol as possible?
Good question. I guess I’m trying to determine if it’s better to lessen the dose or frequency of Rapa to fix the side effects, or take other medications (statins, etc) to treat the side effects?
And are there other metabolic problems caused by Rapa that were not taking care of?
In other, what’s most important? Is inhibiting mtorc2 really bad even if we treat the side effects?
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I think you’re jumping to all kinds of conclusions with very little data (unless you work inside Pharma and have some inside information).
Pharma has already developed many mTOR inhibitors: List of MTOR inhibitors - Drugs.com
And the new drug targets that Tornado Therapeutics has are MTOR inhibitors that they have out-licensed by Novartis. I can’t say I know why Novartis and the other Pharma aren’t yet interested in any longevity drugs, but I suspect it has something to do with higher priorities, and the desire for them to have other investors de-risk the targets beforehand, and then buy the companies if they validate the target.
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It’s an interesting conundrum. I, too, have been hesitant to begin Rapamycin until my LDL is closer to within range. I have been roughly 170 for some time, with this wing my only marker which is off (everything else — glucose, TG, HDL, electrolytes, eGFR, AST, etc is near optimal, and my protein levels are higher but not surprising given I lift heavy every other day). I’ve recently (since Jan) trying to bring it down using citrus bergamot, and I’m actually right now drawing blood to check if it has worked over seven months, so it will be only a day or so until I know if my efforts were useful (spoiler: they weren’t — my LDL went from 172 to 164). .
I’m still unclear if we are merely suffering from a measurement bias, in that this (LDL) is the easy/cheap measurement so we assign causality to ASCVD because that’s where most of the studies have been done using although; there appeas to be much stronger correlations in more expensive/ difficult measurements. Also, I am still curious why Rapamycin increases LDL. If Rapamycin mimics starvation, it makes sense to flood glucose into the bloodstream. But flooding LDL doesn’t make as much sense to me: it is a protective reflex? — we see “higher” LDL appear to help in brain protection/etc even as it correlates with ASCVD risk. Not arguing, just trying to decide when to start Rapamycin, and perhaps to keep LDL higher but routinely clean out with Nattokinase or another plaque reducer.
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They don’t treat the mice in ITP for raised LDL, yet they get life extension. When they add acarbose or metformin they get better results, could be from sugar control. Or something else.
Same with the dogs. And I saw something that indicated the same thing happens to them.
This is by no means a proof, but I think controlling sugar is a good idea. And even if you don’t Rapa should extend life.
We need an intervention that increases mtor 2.
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“As the incidence of diabetes mellitus in TSC patients on mTOR inhibition is only 2.5% in 5 years, we think this should open the debate if regular screening is warranted in this population.”
I was glad to read that, as I find lowering my HbA1c much more difficult than lowering my lipid levels.
As I recall, before rapamycin, calorie restriction was the only proven life extender for mammals.
Currently, my lipid levels are all in the good to excellent range, (depending on your viewpoint.)
So, ignoring the type of diet, these are the things that have lowered my lipid levels while taking rapamycin. Not, necessarily in any order:
Time-restricted feeding 18/6
Calorie restriction. I eat a little less than 1,800 calories daily.
Exercise.
Keep your BMI to 23 or lower.
If you do these things and your lipid levels are still too high, you are an outlier or you are taking too much rapamycin
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@desertshores My father, who is a little younger than you at 76, does everything you do as well - time-restricted feeding (OMAD), calorie restriction (vegetarian), exercise (3x/week gym), and 156 lbs (low BMI). Yet he still has an ApoB of 108. And he hasn’t even started taking Rapamycin yet.
I think everyone’s biology is a bit different and cholesterol is one of those things that we need to work on. I’m trying to get him on a low-dose statin to see if that will help. Unfortunately, I probably have the same issue (ApoB 102). However, I’ve never had a problem with LDL until after starting Rapa. My triglycerides are in range though.
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Hopefully they do not increase LDL preferably even lowers it.
#1 question for Mannick IMO.
I don’t think there is any consensus data to show these reduce LDL
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Since hormones require cholesterol, the body increase PCSK9 to keep as much as possible. Useful in the past in times of starvation. Not so useful now. And if you fake starvation mode with a mTOR inhibitor, with food - especially saturated fat, it is a disaster. That’s a hypothesis.
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Hormone protection is a good theory. I hadn’t really considered that because I was under the impression that testosterone declines during a water fast (and as a male of a certain age, I simplify all hormones to just “testosterone”). So hormones don’t fall as much as they could have fallen during a fast because the body promotes PCSK9s to prevent this? Which is why Rapamycin increases LDL?
If you oversupplement vitamin D when taking Rapamycin, would this blunt the PCSK9 (and LDL) promotion? (I don’t know what D levels this would be)
A related question if this is true: if you reduce LDL to the “Attia 5th percentile” goal using a PCSK9 inhibitor, is it possible to have above-average levels of testosterone (or other hormones)?