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.
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.
“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
@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.
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.
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)?
Statins reduce testosterone by around 3.4%, which is not clinically significant at all. Steroid users in the gym use extreme doses relative to that. So no it does not meaningfully alter testosterone levels. It could be because the excess LDL in circulation is expecting that harder times are coming, or something like that, and not really related to hormone production right now.
It is just a hypothesis, but it makes sense to me. I heard it first from John Kastelein at 57 min at this podcast, a conserve cholesterol hypothesis:
I don’t know, there are plenty of ways of testing this hypothesis, but it is probably more than just vitamin D. mTOR inhibition might be too powerful of a signal as well so it doesn’t matter what other signals you try to send.
Because mice don’t die of cardiovascular diseases. But they can die from diabetes which is why adding acarbose to rapamycin gives such a significant boost to both median and maximum lifespan.
I mentioned three things, not just BMI. I purposely left out diet and supplements, because I think they are secondary to the principles of time-restricted, feeding, exercise, and maintaining a low BMI
You’re right, and it would not be the case for every individual, but for me, and I have been measuring my levels for a long time. There is a strong correlation between my BMI and lipid levels.
“Prior epidemiologic studies have shown that increasing body mass index (BMI) is associated with higher total cholesterol and low-density lipoprotein cholesterol (LDL)”
“Higher BMI was inversely associated with HDL and directly associated with TG. BMI showed no significant association with LDL. Although the association between BMI and both HDL and TG may be explained by insulin resistance, the lack of a significant association between BMI and LDL remains an unexpected finding that requires further investigation.”
I have used a CGM (continuous glucose monitor) and my average glucose levels were significantly lower than indicated by my HbA1c results. In addition, my morning fasting glucose levels are somewhat high, but limited to the hour before I wake up. And eating a meal barely made a blip in raising blood levels. I haven’t used a CGM while taking rapamycin but will at some point.
Agree and disagree with using HbA1c. When comparing the effect of supplements on blood glucose I think it works well, and is certainly better than post prandial glucose. The downside is that you’d have to use the supplement for 6-8 weeks before getting the test.
The A1c test result indicates the percentage of hemoglobin that has become glycated over a period of 3 months. The measure is based on the assumption that everyone’s blood cells last 90 days. Kroger’s point is that this is not the case.
Further he states, “This confused me early in my practice. I was testing blood sugar in three different ways for all new patients: fasting blood glucose, post-meal blood sugar (with a glucometer) and A1c. And I was surprised to see people with completely normal fasting and post-meal blood sugars, and A1c levels of >5.4%.”
Of the 3 measures: HbA1c, Fasting glucose, and post prandial glucose, Kroger thinks that post meal blood levels staying higher than 140 and not returning to baseline being the most pertinent.
I find his reasoning compelling but find it difficult to find corroboration.
There is an additional point that there are different types of A1c test as there are different types of glycated haemoglobin. Some tests test for aldimine and ketoamine, some only for ketoamine. Aldimine is to some extent reversible, ketoamine is much less reversible.
It would seem to me that post prandial glucose would be rather variable depending on what you eat?
I think I will try combining HbA1c and fasting glucose as I compare impact of different Rapa regimens.
The accuracy of HbA1C is a great question for people who are trying to figure out if they need to do anything differently for blood sugar. I have spent the last 10 years progressing from ignorance to denial to attempting many different non-pharmaceutical solutions to now doing everything known to human kind. I will not die from T2D as my father and his brother did.
No added sugar ever
Non-berry fruit only right before exercise
Exercise everyday
Low body fat
Berberine with breakfast (berries and steelcut oatmeal)
IM fasting daily (12 hrs x2)
24 hour fast 1x/week
Metformin
Farxiga
Just me but I’d replace the steelcut oatmeal with eggs. Gundry says they will poke holes in your gut and should be replaced with sorghum. Elsewhere it says soaking and cooking will greatly reduce lectins. Also people with the CGMs say it drives up the glucose.