Rapamycin and risk of cardiovascular disease

The study is associational at best, very weak at true underlying mechanistic pathways. But it was way back in 2007.

“this study highlights the possibility that clozapine’s pharmacological and thus therapeutic activity is associated with serum lipids” They didn’t look at anything related to mTOR, purely conjecture mechanism pathways such as the drug hitching a ride along the VLDL highway and crossing the BBB.

Compare to this paper, which actually proves Rapamcyin dysregulates trigyclerides.

Fast forward 2021:

Mechanistic/mammalian target of rapamycin and side effects of antipsychotics: insights into mechanisms and implications for therapy

https://www.nature.com/articles/s41398-021-01778-w.pdf

“In two previous studies, enhanced mTOR activity disrupted hepatic lipid homeostasis by regulating the expression of sterol regulatory element-binding protein-1c (SREBP-1c) transcription factor. Congruent with this report, other studies found that olanzapine significantly increased SREBP-1c expression, which was suppressed by inhibiting mTORC1 activity with rapamycin. These studies suggest that olanzapine simultaneously activates the mTOR and AMPK pathways that may mediate metabolic complications, and provide evidence that the hepatic mTOR signaling pathway has a central role in the pathogenesis of antipsychotic drug-induced metabolic side effects. In conclusion, multiple lines of evidence indicate that hepatic mTOR signaling is a critical pathway in the antipsychotic-induced glucose and lipid metabolism, which may contribute to weight gain, MetS and other complications”

I haven’t looked too deep, and perhaps they weren’t looking and/or was of inconsequential concern, but in the hundreds of studies of chronic rapamycin dosing cohorts (vast majority cancer, years+ on Rapamycin, lipids dysregulation very common), was CVD NEVER a secondary endpoint finding? Surely this would be a signal outcome? Maybe the data dosen’t even exist.

Does Dr Green ask his patients for CT cardio scan before/after? Given the number of patients he has, this would be some amazing data.

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There seems to be several mechanisms involved which could explain an increase in lipids. The decrease in Prox 1 expression could explain rapamycin and lipids and mTOR activity for the antipsychotics.
Regardless, the psychiatrists have been saying for decades that if you don’t get fat , you’re not going to respond. Turns out that it’s the lipids and not the enormous weight gain that’s correlated with the response. That makes much more sense.

I’d like to see if people who respond to rapamycin also have an increase in lipids. I know that I had a very robust response and my lipids have stayed above pre rapamycin levels. I also had a significant mood improvement in terms of a much better outlook on things. Maybe the lipids carrying the rapa across my BBB.

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By respond, do you mean some positive impact on energy, mood, aches and pains?

These may not equate, however, to longevity benefits, namely, delaying carcinogenesis?

We know from the seminal cancer/GFJ study (WEEKLY dosing), one of the lead doctors stating “lipid, glucose, and lympho dysregulation means we know the drug is working”.

And by working, these oncologists refer to high sirolimus AUC, high trough levels, and p70S6K phosphorylation suppression. I am going to go out on a limb and say no one (outside clinical trial), self hacking with Rapamycin, is going to have this confirmatory data.

So to complete the circle (cancer modulation, all we know as primary target from wild type mice/Rapamycin studies), we’d need to see n=1 “some” lipids, ESPECIALLY TG, glucose dysreguation.

It seems its TG that’s a very strong indicator of potency and mTOR inhibition, not LDL/TC.

Rapamycin, an mTOR inhibitor, disrupts triglyceride metabolism in guinea pigs

“Rapamycin treatment resulted in more than a 2-fold increase in plasma triglycerides (TG) whereas no differences were observed in plasma cholesterol between RAPA and control groups

No mention of LDL/TC.

"Changes in fasting serum glucose and triglyceride concentrations were determined in 127 patients (pts) before, and 4 weeks after treatment with the mTOR inhibitor sirolimus/rapamycin (S). Pts were enrolled in three different trials of S administered to achieve AUC of 1,000-6,000 ng-hr/ml.

Mean & median change: in glucose = 17 & 8 mg/dL, in triglycerides = 51/ & 31 mg/dL."

No mention of LDL/TC.

You mentioned not testing TG for a long time. Would be curious to see your full lipids & glucose panel.

In the cancer/GFJ study, even at 10mg/week Sirolimus ALONE, few people developed hyperglycemia/hyperlipedemia. I think you said you were at 5mg/week?

So far, I don’t have a lab panel showing me crossing into dysregulation, so I don’t believe I’m at tipping point of dosing yet.

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Yes, I need to get an updated lipid panel just to see especially triglycerides.
My fasting blood sugars have been right around 112 since I began rapamycin. HbA1c 5.6-5.7.
The clozapine study was very interesting to me because we’ve observed for so long now that response to the antipsychotics is related to their degree of weight gain. I have a patient who gained 80 lbs. and had a remarkable response. Miraculous really. Her triglycerides were under 100 and jumped to 150.

By working I meant mood, energy, weight loss, and overall mental outlook on life.
If lipids and glucose indicate that the drug is working, then should we be trying to intervene and correct the elevations? I believe that we said in prior posts that we’re willing to accept a certain degree of elevation, but perhaps not an excessive level.
From the studies you referenced it looks like the levels only got very high in a low percentage of patients.

I have the last 8 years of my lipids. Started Rapa in april of 2020. Previous 6 year averages: TG 95, HDL 56,LDL 165,ApoB 126. Next year on Rapa: TG 161,HDL 43,LDL 209,ApoB156. Every number significantly worse. I cut the rate from 6mg/10 days back to 6mg/2 weeks and it resolved.

Other factors of course:
I started taking Niacin and optimized garlic pills.
Tried 3 months of glyNAC
Doctor had me try a month of statins and gave me a month of pcsk9

I really think it was the Rapa, but I’m not really doing science, just sort of randomly thrashing about trying to fix my heart disease. Reminder, I had CAC of 285, one year later CAC 315.

N=1

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Very statistically significant elevations I would say for your lipids, maybe not for the CAC . Did you notice any improvements from the rapamycin while on the weekly dose?

My associate had a significant drop in his CAC score from vitamin k as MK-4, not 7.

You added weight loss…that is associated with inhibition.

Re intervention, I haven’t settled into my thinking on this yet, haven’t dug deep enough, completed a full thought experiment, but some initial considerations.

Interestingly, the oncologist in the cancer/GFJ study I had a brief exchange with, didn’t mention CVD as a concern in his Rapamycin patients…only anemia and ILD. I am inferring on CVD here.
Have read a great many “chronic rapamycin” human studies, don’t recall much on CVD. Extrapolate in this vacuum anything about far weaker intermittent dosing?

If CVD is driven by metabolic syndrome, a “diabetic” profile, and having dysregulated glucose and TG, yet all other markers are excellent (weight, BP, HDL) then “technically” we haven’t tipped the CVD balance?

Frontiers | Rapamycin: A Bacteria-Derived Immunosuppressant That Has Anti-atherosclerotic Effects and Its Clinical Application | Pharmacology (2019)

“Several lines of evidence have demonstrated that rapamycin possess multiple protective effects against atherosclerosis through various molecular mechanisms.”

Do we defacto assume we are blunting cancer with dysregulation, therefore turn our attention to other mortality pathways?

Should I get a lipid subclass analysis…sd-LDL/APOB/ox-LDL to check if tipped into atherogenic risk? TG, TG/HDL are strongly correlated to atherogenic particles.

Looking through the literature for secondary hypertriglyceridemia, cutoffs start at 150 mg/dL. My last TG was 52? Lots of runway??

Relationship between subclasses low-density lipoprotein and carotid plaque

Triglyceride-Rich Lipoprotein Cholesterol, Small Dense LDL Cholesterol, and Incident Cardiovascular Disease

“The risk of both composite outcomes significantly increased across quartiles of TRL-C and sdLDL-C. TRL-C was significantly associated with myocardial infarction (MI) and peripheral artery disease (PAD) hazard ratio [HR]Q4: 3.05, PAD HRQ4: 2.58, whereas sdLDL-C was significantly associated with MI alone (HRQ4: 3.71) Both markers weakly associated with ischemic stroke (IS) Association patterns were similar for continuous exposures and, for TRL-C, among subjects with low atherogenic particle concentrations (apolipoprotein B <100 mg/dl).”

Relationship between subclasses low-density lipoprotein and carotid plaque

Is CT cardio “the” definitive answer?? Would I wait a year and get another CT cardio scan? Keeping progression to < 15%/yr is excellent in those with CAC > 0.

Progression of Coronary Calcium and Incident Coronary Heart Disease Events: The Multi-Ethnic Study of Atherosclerosis

Check my liver and kidney markers are improving, then that’s significant pro health positive. They are intertwined with a great many health pathways.

Do a DEXA scan and check for fat mass, visceral and subcutaneous, observe if metabolic syndrome trending? Make sure not building any fat around organs, eg NAFLD, not visible in the mirror, which is major risk factor diabetes/CVD?

Of course full inflammation markers.

“Evidence has demonstrated that elevated levels of circulating inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) or interleukin-6 (IL-6) independently predict the risk of atherosclerotic cardiovascular disease”

And what about “glucose”? If glucose rising yet loosing weight? Fasting glucose, hbA1c, both?
Check my pancreas marker (c peptide) to make sure beta cells are fine and not being blunted by insulin signalling, ergo, trending to diabetic?Fasting, hbA1c, AUC, cutoffs?

“HbA1c levels were positively associated with carotid atherosclerosis, as assessed by carotid IMT, in an elderly population with normoglycemia. However, fasting insulin and glucose levels were not associated with carotid IMT.”

Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk

“Hemoglobin A1c and cardiovascular disease risk factors were assessed from 1995 to 1997, and cardiovascular disease events and mortality were assessed during the follow-up period to 2003. In men and women, the relationship between hemoglobin A1c and cardiovascular disease (806 events) and between hemoglobin A1c and all-cause mortality (521 deaths) was continuous and significant throughout the whole distribution. The relationship was apparent in persons without known diabetes.

The Association of Hemoglobin A1c With Incident Heart Failure Among People Without Diabetes: The Atherosclerosis Risk in Communities Study

Elevated A1C (5.5–6.0%) was associated with incident heart failure in a middle-aged population without diabetes, suggesting that chronic hyperglycemia prior to the development of diabetes contributes to development of heart failure. The association of A1C with risk of heart failure in our study was independent of hypertension, obesity, other traditional cardiovascular risk factors, and insulin concentration, suggesting direct effects of hyperglycemia on the development of
heart failure

My hbA1c is 5.0…more runway??

If actual true anemia, then what, take IV iron therapy?

And if crossed into risky lymphopenia, does one react, or consider it rejuvenation of HSC for better immune function?

The ITP didn’t intervene and “treat” the mice when dysregulated on Rapamycin, yet they lived longer.

Can Dr B be wrong, some of these dysregulated markers aren’t “benevolent”? He claims below (2019 paper) “no hyperglycemic effects or rapamycin/everolimus in healthy people”?

Reports are now he’s taking 2mg/day? Surely, this is going to significantly dysregulate glucose and lipids, venturing into “chronic” vs “intermittent” preaching.

Fasting and rapamycin: diabetes versus benevolent glucose intolerance (2019)

No hyperglycemic effects of rapamycin/everolimus have been detected in healthy people. For antiaging purposes, rapamycin/everolimus can be administrated intermittently (e.g., once a week) in combination with intermittent carbohydrate restriction, physical exercise, and metformin.”

Hyperglycemia may be a marker of beneficial processes, given that rapamycin ameliorates nephropathy, despite elevating blood glucose levels in a mouse model of type 2 diabetes”

“Furthermore, a mechanistic study in humans showed that prolonged treatment with rapamycin causes hyperglycemia by decreasing insulin production, and insulin production depends on mTORC1. Thus, inhibition of mTORC2 by rapamycin has not yet been proved in humans

That dosen’t seem true:

In human endothelial cells rapamycin causes mTORC2 inhibition and impairs cell viability and function

“A prolonged treatment with rapamycin impairs endothelial function and hinders cell viability. Endothelial damage seems dependent on mTORC2 inhibition”

More Dr B:

"Lamming et al. concluded that rapamycin prolongs life span, despite inducing diabetes-like symptoms. As I previously discussed, perhaps life span is extended “owing to,” not “despite,” these symptoms. Once again, whereas type 2 diabetes shortens life span, rapamycin prolongs it (despite, or maybe owing to, benevolent metabolic alterations).

At the end of the day, living longer for humans is all about all cause mortality reduction.

For humans, I don’t think we can tip the pendulum all the way over to single minded cancer blunting like the wild type mice, and must consider ALL mortality pathways.

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re CAC, 315/285, is 11% progression over 1 yr. < 15% yr is “good”.

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This is what we’re trying to navigate as “humans” vs wild type mice…balancing activities of daily living, all cause mortality risk, and extending longevity, playing with Rapamycin USING science.

When were your two CAC tests relative to dates, rapamycin starting?

Could you already have had a high CAC before starting Rapamycin? 11% increase over a 1 yr period, not sure one can “for sure” associate with Rapamycin.

How is your diet and exercise and did you change it during the 1 yr CCAC interval?

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Started Rapa april 2020. First CAC was Dec 21,2020 (my birthday). 2nd CAC mid Dec 2021.

My Concierge Doc really believes in the lipid thing. He is 65 and thinks he will die of heart disease. For himself he takes a statin and pcsk9 and is actually trying to get his LDL to zero. I think it’s close. My brother and I both told him his brain will quit working and he just laughs and says there is cholesterol in the brain since the drugs don’t affect it.

I had an appt. with Alan Greene and the Covid thing scared me away from NY. I didn’t want to be stuck there for weeks. Then I asked my Doc if I could get Rapa and he said yes right away without even looking up. I just about fell out of my chair. He went next door and told his wife and I thought I could hear her yelling at him. He later told me he wants to take it. I think he’s trying it out on me. Lol. If my experimentation doesn’t work out I absolutely will not blame him.

I had a high CAC before starting Rapa. I just didn’t know it. I was eating a bag of chips a day. I thought I was bullet proof. Lost the 25 lb, still on mostly keto diet (I eat berries and veggies),NO MORE VEG OILS. That’s a hard rule and I read labels. I run 2 miles most days (depending on weather and work load). I’m currently around 9 min/mile.

My Hba1c is around 5.3. I don’t know how it stays that high on my diet. When you all were talking about GLP ra’s I was wondering if I could microdose them maybe and improve my control a little. I think it would be a hard sell for my Doc. By your graph it looks like 5 is optimal.

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Thanks for the further insight into your journey, great you obtained CAC scans, and glad to see dietary/exercise interventions. As I’ve always said, it takes a good scare to change human behaviour. No one is bulletproof.

So only about 9 months on rapamycin before 1st scan. Agreed, your first CAC was previous life totality snapshot, and the one year increase may/may not be rapamycin mediated. It could be completely within your base n=1 trajectory, but at least the rate of progression is LOW.

Do you happen to have some fasting glucose and hbA1c before and after Rapamycin, including after reduced dosing?

Re hbA1c, I’ve been strict keto for 6 years, and the lowest I’ve ever gotten my hbA1c is 5.0. So clearly, even on a very low carb diet, the body (human evolution program) requires a base level of glucose to power some major metabolic functions, especially the brain. We know this from starvation studies. Glucose will drop, but then reach a steady state (even after 40 days starvation), turning on gluconeogenesis from other substrates (fat, protein).

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Thanks MAC for your thoughts and all of your thorough homework/ studies. I’ll read them all tonight.

WRT anemia, my mother is 91 & watches her health closely (this probably has something to do with her still being around at 91). As a result, I’ve learned more about health & aging than I expected to.

In particular, it turns out there is a feedback loop between the kidneys & the bone marrow, in which the kidneys “tell” the bone marrow how much red blood cells to generate. It turns out that the stem cells tend to go wonky (according to this article: Blood cells could be key to aging - Advanced Science News).

The production of blood cells in adults aged under 65 came from 20,000 to 200,000 stem cells, each of which contributed in roughly equal amounts. In contrast, blood production in individuals aged over 70 was very unequal. A reduced set of expanded stem cell clones — as few as 10 to 20 — contributed as much as half of all blood production in every elderly individual studied.

Per se, this has nothing to do with CVD, it’s just information I find interesting & so am sharing it.

[My mother is now being treated by a hematologist for her anemia, which hopefully will help her kidneys.]

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The brain loves its glucose and hypoglycemia is far worse than hyper.
Rapamycin has been shown to inhibit the release of insulin from the pancreas and then gluconeogenesis kicks in.
Some of this is genetic. My FBS prior to rapamycin was 99, same with both of my kids.
What I found interesting was the fact that metformin didn’t budge my post rapamycin FBS of 112 even slightly. Just sits there.

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Hypo in what sense/context? Diabetics, meds induced, fasting?

We know hyper is deadly.

Depending on my keto/fast, and having almost no glycogen reserves, I can sometimes reach to down to near hypo (3.5mmol/L…hypo cutoff is 4.0 mmol) and get the shivers/white fingers. My dietary protocol is entirely about minimizing glucose spikes and AUC, and insulin/IGF-1.

Does metformin impact FBS and/or hbA1c more?

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No, to get a clinically significant hypoglycemia you’d have to be taking insulin or an oral hypoglycemic drug. Rarely an insulinoma. The body won’t let you get severely hypoglycemic from diet.

Thanks for sharing, very interesting study.

"Our findings show that the diversity of blood stem cells is lost in older age due to positive selection of faster growing clones with driver mutations. These clones ‘outcompete’ the slower growing ones. In many cases this increased fitness at the stem cell level likely comes at a cost – their ability to produce functional mature blood cells is impaired, so explaining the observed age-related loss of function in the blood system.”

What drives this fewer/stronger stem cell pool?

Do improved kidney markers on Rapamycin infer anything about this improved cross talk?

I haven’t read the full study, but we also know, mTOR hyperactivation in old age drives hematopoietic stem cell exhaustion/senescence, and that Rapamycin rejuvenates this pool.

mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells

“Together, our data implicate mTOR signaling in HSC aging and show the potential of mTOR inhibitors for restoring hematopoiesis in the elderly.”

Hba1c is within .1 of 5.3 very consistent even from back when I was a bad boy.
Fasting glucose really shows no pattern. As low as 84,85 and the highest was 97 with similar numbers before and after Rapa.

First, I must repeat my paraphrased advice to any younger person taking supplements of any kind: If it ain’t broke you’re not going to fix it. Even if a supplement is doing you a long-term good, you may not be experiencing any immediate benefits.

So, having taken rapamycin for approximately seven months, at ever-increasing doses, I don’t feel like I’ve discovered the “Fountain of Youth” as far as increased energy, etc., but it has had some unexpectedly positive results.
Taking rapamycin has eliminated my “essential” age-related hand tremors.
Eliminated my need to go to my dermatologist for treating chronic actinic keratosis.
Effortlessly maintaining my desired weight without worrying about my diet. (As teenagers are often able to do.)
After six months I am sleeping better than I did at 40.

Here are the latest two of my lipid panels; the first was taken ~ approx 2+ years ago and the latest was taken a few weeks ago. As you can see my lipids have increased rather dramatically after taking rapamycin for ~ 7 months.

Collected: 2/13/2020 09:30


Collected: 05/26/2022 08:48

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