Rapamycin and risk of cardiovascular disease

That’s a huge leap of logic. During sepsis one tends to lie on their bed a lot instead of sitting at their disk, so is sitting good for your immune system? :clown_face:

Actually, there are many doctors and PhDs that advocate low-carb diets.
My own opinion is that low-carb diets are not for everyone. I am currently on a low-carb, carnivore-heavy diet and I have never felt better and it has not raised my cholesterol or lipid numbers.
I think some people have a genetic disposition that enables them to do well on a low-carb diet.
One of my genetic indicators is Lp(a). It is so low that my lab does not even give me results because it is below their measurement threshold. My ancestors are of Northern European extraction and lived mainly on meat and dairy products for generations.
That is why I tend to believe the right diet for someone is somewhat based on their heritage.

If you want to see some real doctors extolling the low-carb diet, watch some of the videos from the reference below. It apparently is a bigger thing in Australia than in the US.

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We have a miscommunication. I have no objection to low-carb diets, and neither do the medical societies: PhD doctor Diamond and his colleagues are not just arguing for LC, but arguing that in the context of LC LDL-C/apoB doesn’t matter for CVD.

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Contrarian grifters will of course deny scientific consensus because their target viewership are anti-science suckers.
I am not against keto but ignoring apoB is downright deadly.

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https://www.ahajournals.org/doi/abs/10.1161/01.atv.12.3.341

https://www.jci.org/articles/view/118556

It rained last night so I have a little time today. These are some of the references he listed.

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So, do you have evidence that the keto diet alone drives up apoB? Honestly, I noticed no effect. Probably because I maintain a relatively low body fat. Obesity and junk sugar-loaded diets, IMO, are the main contributors to a high apoB unless there is some genetic factor involved.

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These are mouse studies using mice who have high LDL-C because their LDL receptors have been knocked out. In the JCI paper, LDLR-/- mice “challenged with LPS had an eightfold increased LD50 [after a lethal challenge with LPS]” and inflammatory cytokines “were decreased twofold. LDLR-/- mice had significantly lower and delayed mortality than control mice after infection with Klebsiella pneumoniae.” They provide evidence that it’s the high LDL-C that does it, not some other aspect of the model.

The ATVB paper finds that LPS causes less inflammatory activation of monocytes in the same mice. This is actually in conflict with the JCI paper, which finds that “the LPS-
stimulated in vitro production of cytokines by peritoneal macrophages of LDLR-/- mice was significantly increased compared with controls.”

Another paper used both the LDLR-/- mice and an APOE knockout (both of which have high levels of LDL-C but for different reasons:

To determine whether higher levels of serum cholesterol could enhance the organ burdens of [the Lyme disease (Borrelia burgdorferi) and relapsing-fever (Borrelia hispanica) agents] in laboratory mice

Both apoE- and LDLR-deficient mice infected with B. burgdorferi had an increased number of spirochetes in the joints and inflamed ankles compared with the infected wild-type (WT) mice, suggesting that mutations in cholesterol transport that result in high serum cholesterol levels can affect the pathogenicity of B. burgdorferi. In contrast, elevated serum cholesterol did not lead to an increase in the spirochetemia of B. hispanica. In the LDLR-deficient mice, the course of infection was indistinguishable from the WT mice. However, infection of apoE-deficient mice with B. hispanica resulted in a longer spirochetemia and increased mortality. Together, these results argue for the apoE deficiency, and not hypercholesterolemia, as the cause for the increased severity with B. hispanica. Serum hyperlipidemias are common human diseases that could be a risk factor for increased severity in Lyme disease."
https://www.pnas.org/doi/10.1073/pnas.1502561112

In a different mouse model,

PCSK9 inhibition reduces mortality in septic mice, presumably through increased hepatic clearance of pathogen lipids due to increased lipoprotein receptor concentrations. … Wild-type, PCSK9 knockout (KO), and transgenic (Tg) mice that overexpress PCSK9 were subjected to sham surgery or cecal ligation and puncture (CLP)…

Results: Overexpression of PCSK9 in mice increased liver and kidney pathology, plasma IL-6, ALT, and TAT concentrations during sepsis, whereas PCSK9 KO mice exhibited reduced bacterial loads, lung and liver pathology, myeloperoxidase activity, plasma IL-10, and cfDNA during CLP-induced sepsis. … Dyspnea, cyanosis, and overall grimace scores were greatest in septic mice overexpressing PCSK9, whereas PCSK9 KO mice retained core body temperature during sepsis.
Differential Expression of PCSK9 Modulates Infection, Inflammation, and Coagulation in a Murine Model of Sepsis - PubMed

So the mouse evidence is mixed depending on the pathogen and the model. In human studies the evidence seems to point to either no effect or to high LDL-C driving worse outcomes in severe infections:

"We evaluated the impact of PCSK9 loss-of-function (LOF) genotype on both 1-year mortality and infection-related readmission (IRR) after an index sepsis admission. … In the Derivation cohort, patients carrying multiple PCSK9 LOF alleles showed lower risk for the composite outcome 1-year death or IRR (HR: 0.40, P = 0.006), accelerated reduction on neutrophil counts (P = 0.010), and decreased levels of PCSK9 (P = 0.037) compared with WT/single LOF groups. Our meta-analysis revealed that the presence of multiple LOF alleles was associated with lower 90-day mortality risk (OR = 0.69, P = 0.020).
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(18)30536-X/fulltext

Among 10,924 Black participants, PCSK9 LOF variants were present in 244 (2.2%). Serious infection hospitalizations occurred in 779 participants (14 with PCSK9 variants and 765 without). The presence of PCSK9 variants was not associated with infection risk (adjusted HR 0.68; 95% CI: 0.38-1.25). Among participants hospitalized for a serious infection, the presence of PCSK9 variants was not associated with sepsis (adjusted OR 7.31; 95% CI = 0.91-58.7).
PCSK9 loss-of-function variants and risk of infection and sepsis in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort - PubMed

Those are observational studies. Here is a high-stakes clinical trial:

In this double-blind, placebo-controlled, multicenter pilot trial, 60 patients hospitalized for severe COVID-19, … were randomized 1:1 to receive a single 140-mg subcutaneous injection of evolocumab [PCSK9 inhibitor] or placebo. … Patients randomized to receive the PCSK9 inhibitor had lower rates of death or need for intubation within 30 days vs placebo (23.3% vs 53.3%, risk difference: –30%; 95% CI: –53.40% to –6.59%). Serum IL-6 across time was lower with the PCSK9 inhibitor than with placebo (30-day decline: –56% vs –21%). Patients with baseline IL-6 above the median had lower mortality with PCSK9 inhibition vs placebo (risk difference: –37.50%; 95% CI: –68.20% to –6.70%).

Impact of PCSK9 Inhibition on Clinical Outcome in Patients During the Inflammatory Stage of the COVID-19 [IMPACT-SIRIO 5]; NCT04941105)
PCSK9 Inhibition During the Inflammatory Stage of SARS-CoV-2 Infection - PMC

Collected data from clinical trials revealed that treatment with PCSK9 inhibitors has beneficial effects in lowering LDL-C via inhibition of LDL-receptors (LDL-R), an antiviral effect on HCV infection via down-regulating the surface expression of LDL-R and CD81 on hepatic cells, and a positive association with increased inflammatory responses, as well as with septic shock by down-regulation of hepatocyte LDL-R.
PCSK9 and infection: A potentially useful or dangerous association? - PubMed

In considering the above papers, it bears remembering that statins and low-saturated-fat diets also lower the concentration of LDL receptors on the liver.

In the bigger picture, cardiovascular disease kills far more people than infections in every adult age group — and it results from cumulative exposure to LDL-C/apoB. By contrast, if you really want to, you can always drop your statin when you have a severe infection.

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Keep cholesterol low until immune system starts to go, then let cholesterol rise again to help immune response? Or wait until you have 10 years left. Too early for high cholesterol for me right now.

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I heard high saturated fat in diet (regardless of calorie balance), was a driver of higher apoB.

Here’s Alan Flanagan PhD talking about liver fat (and saturated fat).

One man’s opinion, cherry picking, as we all do.
I have never had fatty liver disease or an apoB outside of the normal range while on a low-carb diet.
On the other hand, I did on a high-carb diet. n=1

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@desertshores If you take Rapamycin + Metformin, it pretty much stops any formation of fatty liver. Both compounds retard fatty liver, but taken together, it is a full preventative for this common disease.

At least in fatty liver prone mice. :wink:

Here’s a short clip of Ronald Krauss talking about LDL picking up LPS (endotoxin) and disposing of it when taken up by the liver. He hypothesizes that statins improve clearance of LPS by upregulating LDL clearance.

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This forum supports the same approach with rapamycin. You use it when healthy and drop it before an operation or when you are infected.

We already know that rapamycin-driven glucose disregulation is a significant issue. Why would we expect rapamycin-driven lipid disregulation to be any different?

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Only 3.8%-1.9% had an increase in LDL in the rapamycin treated group compared to placebo, across all doses in the Mannick study:

Why does it seem like so many here have an increases in LDL cholesterol? Is it something with rapamycin vs. everolimus? Do we only hear from those with side effects? Does anyone know?

I have to admit my view has been very skewed based on the anecdotes here, where I think almost everyone gets it… and maybe falsely so.

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One thing that worries me is that I find my cholesterol varies. Not by that much but it goes over and under the 3 mmol/l that is the threshold in the UK. Hence if I count only the times it goes over I have a number of increases, but I am not that bothered as it tends to go down as well.

Hence unless you know the magnitude of the increases and whether it remains higher it is not that useful as a metric.

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Is that LDL cholesterol or total cholesterol?

I wouldn’t be so certain that you would be the outlier of those who is at risk from LDL cholesterol, basically not median risk for cardiovascular disease from LDL. The median should be the expectation for all of us, and it requires very superior evidence to convince me at least otherwise, on par with the RCTs and MR studies that the risk is based on. You could do a CAC scan to check if you’re somewhat protected with a negative CAC, but it only does so IMO above ~70 yrs old, basically it has been delayed enough for normal lifespan. A positive CAC means advanced cardiovascular disease according to Allan Sniderman.

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My LDL-C and TC dropped significantly (-15%) on rapamycin in 6 months without any significant dietary and lifestyle changes. If anything I increased calories from 20% CR to 10% (about 240 calories).

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If only a few percent get an increase in lipids it’s not a big problem, of course it is for them, but not for rapa in general.

I can’t even believe people chose to defend increase in lipids by rapa if only a few percent gets this side effect. I thought it was more common based on how much rationalizing was going on, now it is even more absurd.

I believe increase in lipids is mostly mitigated by your metabolic health. If your metabolic health prior to rapamycin is not perfect it will show immediately. mTOR is central regulator of metabolism and if you can imagine turning that down might just not be that good if your metabolic health is already impaired.