Rapamycin and risk of cardiovascular disease

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#143

Here’s a paper on ACM/LDL, with a lipid lowering intervention included.

Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study

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“Most studies investigating the relation between levels of LDL-C and the risk of all cause mortality have found no association, or an inverse association. Our study showed that the inverse association can be explained by the increased risk of all cause mortality associated with low levels of LDL-C rather than representing an actual decreased risk at high levels of LDL-C. Previous studies on the association between total cholesterol and risk of mortality showed a reversed J shaped or U shaped association, with the highest risk of all cause, cancer, and other mortality found at the lowest levels of total cholesterol, although positive, inverse, and no association with cardiovascular mortality have been reported. Also, we have recently found a similar U shaped association between levels of high density lipoprotein cholesterol and risk of all cause mortality. In our study, in individuals receiving lipid lowering treatment, the association between low levels of LDL-C and an increased risk of all cause, cancer, and other mortality was weaker than for individuals not receiving lipid lowering treatment. Any increase in levels of LDL-C, however, was associated with an increased risk of cardiovascular mortality but the 95% confidence intervals were wider and included a hazard ratio of 1.0 for all cause, cardiovascular, and other mortality at any concentration of LDL-C. This finding indirectly indicates a non-causal association and suggests that the reduction in levels of LDL-C caused by lipid lowering treatment does not explain the increased risk of mortality at low levels of LDL-C but rather low LDL-C levels is a predictor for mortality. Hence it would be incorrect to use our data as an argument against the use of lipid lowering treatment in the prevention of atherosclerotic cardiovascular disease and mortality. A recent meta-analysis of studies in individuals at high risk of atherosclerotic cardiovascular disease showed that more intensive lowering of levels of LDL-C was associated with a greater reduction in the risk of all cause and cardiovascular mortality. The remaining association between low levels of LDL-C and cancer mortality together with the association between very low levels of LDL-C and an increased risk of cancer (fatal and non-fatal) supports the hypothesis of a decrease in LDL-C levels because of debilitation and illness. Together, these results indicate the importance of assessing the absolute risk of atherosclerotic cardiovascular disease in deciding when to use lipid lowering treatment, rather than starting treatment based solely on a moderate increase in levels of LDL-C.”

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#145

Looks like you posted that twice😁

Seems to argue exactly what I’m saying, doesn’t it?

Pharmacologically lowering LDL in high-risk individuals (the lower the LDL the better) decreases mortality. Low LDL to begin with is most likely a marker of frailty.

Conversely, increasing LDL with rapamycin could be detrimental (especially if there are CVD risk factors). Maybe the anti-inflammatory effects of the rapa will counteract this (I hope so, but we have no idea if the doses we take will do this), so it still makes sense to me to take something to blunt or reverse this increase if it’s significant. Especially if one can do it with a non-statin supplement.

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#146

Agreed, I doubt it’s malnutrition as “causative”. The paper referenced in the video:

Non-HDL cholesterol paradox and effect of underlying malnutrition in patients with coronary artery disease: A 41,182 cohort study

They use some sketchy “CONUT” nutritional status biomarker to justify lower LDL-C as causative.

CONUT: A tool for Controlling Nutritional Status. First validation in a hospital population

“The nutritional status assessment. It is done automatically by the tool using two biochemical parameters (serum albumin and cholesterol level) and one immune indicator (total lymphocyte count). Serum albumin is used as an indicator of protein reserves. Cholesterol is used as a caloric depletion parameter. Finally, total lymphocyte count is used as an indicator of loss of immune defences caused by undernutrition. The albumin has double the rating than cholesterol and lymphocytes, as it provides more “weight” as an undernutrition indicator. Anyway, the relative weight of these scores will be probably adjusted in the future, by means of stepwise multivariate analysis. We still don’t know if CONUT can be applied to infants or elderly until new studies validate the tool in those group of ages. No relationship was found between Body Mass Index (BMI) and undernutrition in our study population, assessed by any of the three methods used. BMI could be a good indicator of medium/long term undernutrition in general population, but it does not seem to be so indicative in a hospital environment”

#147

That is of some concern. I think that our hope here is that daily and weekly use are totally different animals with very different adverse effects.
At least that’s our hope. I believe that Alan Green has his patients check their HOMA -IR. It would be good to know .

#148

Sorry about that!

“high risk” individuals, what is that exactly? I (n=1) would take a holistic approach and review diet, insulin resistance, VO2, stress test, BMI, visceral fat, full CVD risk biomarkers, and especially a coronary calcium score baseline, before introducing pharma. LDL as sole causative CVD mediated proxy is far too ambiguous and has all sorts of confounders.

As for rapamycin dysregulation of lipids/glucose being “causative” to CVD and intervening with pharma…I haven’t decided what I’d do if faced with this threshold.

#149

Don’t forget family history! And yes, coronary calcium (or even better, one of the upcoming newer imaging methods that can also visualize soft plaque) would be an excellent start.

Specific lowering of LDL by PCSK9 inhibitors is an example of the validation of LDL as a cause of CVD. There’s no anti-inflammatory effect of PCSK9 inhibition, but it lowers plaque and CVD events.

#150

If you want to throw the whole LDL/lipid hypothesis on it’s head, have you ever read papers by Subbotin? Pretty compelling stuff from a pathological progression of CVD. Lowering LDL is not the causative intervention pathway.

I am not convinced LDL lowering per se is the prime target of some of these pharma interventions, but some other mechanistic pathway (s).

“Coronary atherosclerosis starts with pathological intimal expansion, resulting in intimal hypoxia and neovascularization from adventitial vasa vasorum, facilitating lipoprotein extraction by previously avascular deep intimal tissues.”

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Neovascularization of coronary tunica intima (DIT) is the cause of coronary atherosclerosis.
Lipoproteins invade coronary intima via neovascularization from adventitial vasa vasorum, but not from the arterial lumen: a hypothesis

Excessive intimal hyperplasia in human coronary arteries before intimal lipid depositions is the initiation of coronary atherosclerosis and constitutes a therapeutic target

https://sci-hub.se/10.1016/j.drudis.2016.05.017

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#151

Indeed family history and genetics.

#152

MAC
I think we’re on the same page here. The article you posted concludes the need to assess the absolute cardiovascular risk and don’t just treat based on a moderate level of LDL increase.
I very much agree that we need to assess the entire picture and decide based on a whole variety of factors. One of the big risks unfortunately is the one that we can’t control, and that’s a strong family history.
Lipids are certainly a part of the atherosclerosis process but they need to be viewed in context ( unless extremely high through a familial disorder). There are plenty of people with elevated lipids who aren’t having strokes or heart attacks. It’s a risk among many.

#153

Thanks Mac, very interesting. Hyperplasia of the smooth muscle intima would support the Blagosklonny theory of hyperfunction and would also support a protective rapamycin effect. That’s assuming weekly and not daily dosing.

#154

Interesting hypothesis (and the paper is literally labeled “a hypotheses”), but quantity and quality of evidence matters. There are mountains of experimental evidence showing that LDL is a key player in CVD. It’s a complicated process for sure, with multiple steps and multiple potential targets (LDL, oxidative stress, inflammation, neo vascularization, etc). I’m not saying LDL is the only target or the only cause of CVD, but it’s certainly the target with the most experimental evidence behind it (so far) when it comes to lowering it to treat CVD.

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#155

Actually, hypertension is probably the major causative factor for cardiovascular disease and isn’t related to rapamycin.
I’m trying to keep mine in the 100/60 range - without meds . https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.119.14240

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#156
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#157

Sobering study. But again, chronically ill patients on daily immunosuppressive agents, and some very high dosing in the in vitro data.

Seems the evidence in this paper is strongly associated with mTOR2 suppression, and glucose/insulin dysregulation and implies NODAT (new onset diabetes) from change in β-cell function/toxicity via “chronic” administration.

“Given the suggestion that both rapamycin b-cell toxicity and insulin resistance may be mediated predominantly via mTORC2 rather than mTORC1 (36,55), the question arises whether an mTORC1-specific inhibitor would retain the immunosuppressive effects of rapamycin without any
mTORC2-mediated toxicity. However, this involves the assumption that the immunosuppressive effects of rapamycin are indeed mediated predominantly via mTORC1 which is not currently known”

Currently was in 2013, 9 years ago.

Fast forward 2018…

mTORC2 Signaling: A Path for Pancreatic β Cell’s Growth and Function

https://sci-hub.se/https://doi.org/10.1016/j.jmb.2018.02.013

“While mTORC1 signaling has been extensively studied in islet/ β-cell biology, recent findings demonstrate a distinct role for mTORC2 in the regulation of pancreatic β-cell function and mass. mTORC2, a key component of the growth factor receptor signaling, is declined in β-cells under diabetogenic conditions and in pancreatic islets from patients with type 2 diabetes. β-cell selective
mTORC2 inactivation leads to glucose intolerance and acceleration of diabetes as a result of
reduced β-cell mass, proliferation and impaired glucose-stimulated insulin secretion”

Seems mTOR2 to be highly implicated.

Hold on…2018 on MTOR1 (still looks like it shows how diabetes hyper elevates TOR1, but blunting via TOR1 inhibition can trigger TOR2 suppression)

mTORC1 Signaling: A Double-Edged Sword in Diabetic b Cells

https://www.cell.com/action/showPdf?pii=S1550-4131(17)30672-1

“Genetic or chemical inhibition of mTORC1-S6K1 signaling restores insulin secretion in isolated
human islets from patients with T2D, suggesting that elevated mTORC1 impairs b cell function (Yuan et al., 2017). The higher mTORC1 activity observed in islets and b cells of individuals with T2D is consistent with findings in animal models of T2D and is probably due to chronic hyperglycemia”

“But the critical function of mTORC1 as regulator of nutrient sensing and cellular metabolism under physiological conditions makes mTORC1 a challenging therapeutic target, and the establishment of an ‘‘mTORC1 therapeutic window’’ to target only the ‘‘pathogenic arm’’ of mTORC1 signaling in T2D will be very difficult. Moreover, no specific mTORC1 inhibitor
has been discovered so far. One important consideration in the development of mTORC1-targeted therapeutics is to what extent and how specifically a given drug can achieve its intended action without off-target adverse effects”

“The emerging paradigm by which chronic mTORC1 activation can cause b cell failure in T2D has underscored the importance of understanding the complexity of the mTOR network in the regulation of b cells’ metabolic plasticity in response to inappropriately elevated nutrients. This complexity includes the diversity of nutritional inputs (glucose, FFA, amino acids, etc.) and mechanistic outputs, as well as the transformation of initially anabolic mTORC1 signals into deleterious outcomes. While physiological mTORC1 stimulation is essential for the maintenance of b cell physiology and acts as a homeostatic signal for b cell adaptation, chronic mTORC1 activation may lead to progressive loss of b cell function and mass by several mTOR-regulated processes such as impaired insulin and mTORC2 signaling, impairment of autophagy, and development of unresolvable ER stress”

I am measuring the basic glucose/insulin parameters in my panels, and if trending towards dysregulation, would most certainly add a c-peptide test.

But wait, hasn’t the “gold standard” ITP on chronically treated Rapamycin mice, notwithstanding primary longevity extension end point, measured mTOR2, glucose and insulin dysregulation, pancreatic b-cell function/apoptosis? Is this dynamic at play in these murine models, yet manifests as eventual general neoplasms/cancer, not granulated for b-cell function?

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#158

Hypertension is a nasty manifestation of impending CVD, but yet again, just a downstream effect…not fundamentally causative? What causes narrowing on vasculature?

Aside from any genetic predisposition, I have my money on insulin resistance and metabolic syndrome, a constellation of whole body dysfunction, chronic in sedentary over-feed, high glycemic western society, all lifestyle mediated.

Conspiculously absent…LDL.

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#159

Yes good point, I left out hypertension as a major cause of CVD. Doesn’t change the point about LDL as a major modifiable cause, though.

#160

Yes, having high LDL will likely “accelerate” the hyperplasia of the tunica intima…but it’s not singularly CAUSATIVE.

I am on a strict keto diet, daily 24 hr fasting, very high exerciser, stellar health and biomarkers, including VERY low remnant cholesterol, TG, and TG/HDL, yet my LDL is high because of the mode of dietary energy trafficking in my system. No family history.

Others have similar experience.

“A high TG/HDL cholesterol ratio and an LDL cholesterol profile characterized by small particles now comprise the dominant dyslipidemia among those with ASCVD.”

“Explanation of LMHR involves physiological mechanisms relating directly to energy metabolism. By analogy, sodium-glucose cotransporter 2 (SGLT2) inhibitors, which promote fat oxidation and ketosis, increase LDL cholesterol (and, interestingly, reduce ASCVD risk), raising the possibility that a shift in substrate oxidation from carbohydrate to fat intrinsically elevates LDL cholesterol ([28](javascript:;)). Thus, reduced intake of carbohydrate may increase systemic trafficking of lipid energy through VLDL lineage particles coincident with high lipoprotein-lipase–mediated remodelling of VLDL into LDL and HDL, and resulting in a profile of elevated LDL cholesterol and HDL cholesterol, and reduced TG. We speculate that this effect may be greatest in lean, insulin sensitive individuals with high energy demands, a possibility consistent with other research”

Should I go on statins to lower my LDL?

I have a next 5 yr coronary calcium later this year.

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#161

Seems reasonable to me to wait and see what your calcium score is, but if it were me I’d move up the scan sooner if your keto status is a new thing since your previous calcium scan 5 years ago, just in case things have gotten worse. Either way, unless your apoB is through the roof I wouldn’t choose a statin first, but rather try amla extract and/or citrus bergamot and see if that does the trick before turning to pharma (and even then, maybe ezetimibe before statin, again depending on how high your numbers are).

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#162

I doubt it will remain the same just from aging, but will be keenly interested to look under the hood!

I haven’t checked apoB in a while, will add next panel.

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#163

Re inflammation, my hsCRP is basically zero over the years of my lifestyle changes, 0.1-0.2.

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