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)?
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.
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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.
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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.”
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Have you considered that HbA1c can be a flawed indicators? See Why Hemoglobin A1c Is Not a Reliable Marker - Chris Kresser.
Chris Kesser makes the argument that after meal glucose levels are a better indicator of metabolic health.
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.
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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.
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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.
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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.
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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
What am I missing?
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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.
I know the fiber is good.
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I do eat eggs with my breakfast
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Do Metformin, Berberine, and Farxiga do anything to prevent diabetes? Or just treat it? I think Metformin can be preventative, but not approved for that.
Supposedly they keep blood sugar down, to save my pancreas among other benefits. I don’t want to use a keto diet; I want to build metabolic flexibility. I need to get my sleep working and stay on the IM and short- term fasting program. Fasting has always been a good reset for my insulin sensitivity.
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great thought process, however, since rapamycin is known to have an undesired impact on both in some populations regardless, perhaps a better marker or two would be something related to inflammation CRP and immunity Neutrophil?
Those seem like reasonable things to track and are usually tracked as part of phenotypic age calcs, so cheap and easy to do.
What I’d really like to track (as doses get higher) are TREGs. Dudley lamming has suggested this as something we should track… but I can’t find anyone who provides these blood tests at any reasonable costs. Dudley seems to think these are the best way to track immune system function.
None of the regular blood test resellers offer it (from what I can find). Perhaps I’m looking for the wrong thing (I just search on “tregs” in the search bars for these companies.
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