That’s a good point and question: the heart disease risk may be accounted for in other biomarkers such as glucose and triglyceride, which make the LDL reading redundant when they are all collected together - the table I posted was for the bicorrelations among multiple variables.
But if the only measurement you have is for LDL, it may still be a good predictor of heart disease risk. However if you have the choice of what biomarkers to measure, I think the table suggests it is better to focus on glucose/triglyceride vs LDL
I am aware of the controversies regarding this chart and the optimal LDL level in general. As I said, “overall if I had to guess, I would tend towards lower LDL is better”.
Also there is no such thing as “debunking”. There is only conflicting research, the most recent of which suggests lower is better. But the tide can shift the other way in the future as it did before here.
Since we are much closer to the 4.7ppm dose that produces a 3% and 16% median LS increase in males and females respectively (in mice), this seems to suggest female users of rapamycin on this forum may experience much stronger benefits/effects from rapamycin use. I wonder if that is the case in practice? Made me notice there a fewer posts on rapamycin effects by females on this forum.
After half a century of research, it’s become pretty clear that the lower your apoB the better. Whether there is a lower limit or not is unknown, but it’s definitely lower than whatever clinical guidelines recommend today.
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?
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].
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.
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.
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.
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?
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.
