Depends on how he’s defining hyperglycemia. Is it a HbA1c of 6 in his definition?
I can’t really remember him addressing lipids specifically. I believe I saw a study that showed an increased incidence of CAD in renal transplant patients on rapamycin c/w cyclosporine. Do mice get heart disease or just cancer?
From what I can glean, looking at his references citing cancer/transplant studies, 160 mg/dl glucose.
90%+ neoplastic lesions wild type. Of course, they show cardiovascular aging, but that’s not what causes mortality…in mice.
From the Rapamycin/cancer/GFJ study (weekly high dose Rapamycin) re hyperglycemia and hyperlipedemia, the two highest side frequency side effects, although a smaller % Grade 3/4 toxicity.
If pre- diabetes indicates that the glycocalyx, kidney, pancreas and vasculature are already impaired permanently, would that by extension suggest that insulin resistance (not yet pre-diabetes) has to a lesser degree also caused permanent damage? And if so does that imply irreversible?
If you’re clinically insulin resistant/metabolic syndrome, I will argue you’ve already done plenty damage. Yes, you CAN reverse insulin resistance with diet/exercise/weight management, but that may not reverse the/all physiological damage. Get as far away from insulin resistance as possible!
I am taking rapamycin in the hopes of extending my health and/or life span.
The fact that rapamycin is raising my lipid levels may mean rapamycin knows something.
Even though my lipid levels have been raised, including HDL-C, my ratios remain in the good range for all-cause mortality.
Recent studies indicate that the ratios have a U-shaped curve for ACM, especially in the elderly.
I am quite happy with my current ratios.
My current ratios after ~7 months of taking rapamycin
TC/HDL-C = 2.62
TG/HDL-C = 2.52
LDL-C/HDL-C= 1.23
“The association between levels of LDL-C and the risk of all cause mortality was U shaped, with low and high levels associated with an increased risk of all cause mortality”
The concentration of LDL-C associated with the lowest risk of all cause mortality in multivariable adjusted analyses was 3.6 mmol/L (140 mg/dL) in the overall population and in individuals not receiving lipid lowering treatment.
Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study
Lipid-lowering treatment to the end? A review
of observational studies and RCTs on
cholesterol and mortality in 80±year olds
"Low TC (<5.5 mmol/l) is associated with the highest mortality
rate in observational studies of 80±year olds"
(5.5 mmol/l = 99 mg/dl)
https://academic.oup.com/ageing/article/39/6/674/10228?login=true
In my case you’re preaching to the choir. I’m even wondering if the lipids confer an advantage.
There is a whole cadre of doctors worldwide, especially those who practice and/or recommend a keto diet that thinks the importance of low cholesterol is overtated.
This thread is Rapamcyin and CVD. We have a documented n=1 on Rapamycin with dysregulated lipids confirmation.
We need the hard data (“science”) on change in CVD risk to elevate this discussion. It’s very likely the matter won’t be settled, but bringing objective metrics, we can certainly build on this very important topic as more users may be increasing dosing protocols.
Circulation published a study looking at the importance of reducing individual risk factors for cardiovascular disease.
Lowering LDL by 30% will reduce your 10 year cardiovascular risk by an absolute number of 2.7%. That’s not , obviously, taking into account the concomitant protection that may be conferred by rapamycin to reduce that risk even further.
Once again, lipids are a risk factor, not a death sentence.
2.7% reduction when risk is 10.7% is a 25% relative risk reduction. Cutting my risk by 25% is pretty huge IMO. And that’s just with 30 point LDL decrease.
Another 30% with keeping blood pressure under control, and now risk is less than half of what it was over that 10 year period. Note we don’t have any such data for rapamycin, just speculation and wishful thinking.
Absolute risk is much more telling than relative risk which should be abolished it’s so misleading. If you go from 1 person in a million to 2 in a million you’ve doubled your relative risk.
They even called the absolute risk reduction “ modest”.
There are limitations in that they didn’t look at ApoB and it was over 10 years and not say 20 or 30 which could have changed the result.
Granted, the human data on rapamycin is limited, but multiple studies over many species, including mammals, is more than just wishful thinking. Is it not?
It’s the “may” that we’re trying to discern. You can find dozens of papers and studies supporting higher LDL, TC in older cohorts and longevity. Sounds like confirmation bias.
But where are the facts Rapamycin induced lipids dsyregulation is benevolent?
How many of these “LDL/TC type” studies look under the hood at the true underlying risk factors like apoB, sdLDL, ox-LDL, CAC progression rate and 10yr CVD risk? Or an even more in depth cardio risk profiling offered by the Cleveland Heart Clinic.
I don’t recall they looked at these metrics for the wild type ITP mice? So the takeaway: Rapamycin increases longevity, translatable to humans, happily accept the cause of death.
However for us humans who can get neurological diseases late in life, I certainly don’t want to get AD at normal epidemiological age, and be kept alive (and be a longevity statistic) ONLY because of the physical reserve benefits conferred by Rapamycin? That’s not a tradeoff for me. I want AD pushed out by Rapamycin. I’d like to know if Rapamycin increases my risk odds, either by some core neurological pathway mechanism (eg. TREM2) OR via dysfunctional cerebral cause by peripheral intervention.
Why do the studies showing cardiovascular benefits or Rapamycin administration in mice have to resort to such dsyfunctional, transgenic mutant, genetic fantasy compromised mice?
mTOR drives cerebral blood flow and memory deficits in LDLR (-/-) mice modelling atherosclerosis and vascular cognitive impairment
Cardioprotective effects of dietary rapamycin on adult female C57BLKS/J-Leprdb mice
So I went back at looked at one of the early seminal Rapamycin/mice/longevity studies in wild type mice.
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice (2009, Richard Miller)
I dug out the supplementary data where they reported on pathological cause of death.
Herein. As expected, cancer related represents 90% of deaths in both control and Rapamycin, but sub group analysis shows cardio related deaths DOUBLE IN THE RAPAMYCIN COHORT?!
Not only that, certain types of caners are higher in the Rapamycin cohort (Fibrosarcoma, *Hemangiosarcoma, Lymphoma, Pulmonary Tumour) showed higher prevalence than in control mice?
*Hemangiosarcoma (Hemangiosarcoma - Wikipedia) Hemangiosarcoma is a rapidly growing, highly invasive variety of cancer arising from the lining of blood vessels; that is, blood-filled channels and spaces are commonly observed microscopically. Sounds nasty.
Yes, ok, they lived longer on Rapamycin, but dosen’t sound cardio benevolent (nor pan cancer benevolent) to me for these wild type mice. Of course, we’re talking MICE and CHRONIC Rapamycin administration. But these wild type mice don’t have metabolic syndrome or are sedentary I might add, and this could be a significant confounder in human translation.
The higher prevalence of cardio related causes of death in these mice didn’t happen on the last day of their lives…they likely slowly manifested, just like in humans. So some interesting dynamics at play re Rapamycin initiating more cardio related degenerative pathways, yet still pushing their mortality outcome to later in life?
So, this would reinforce the point of MEASURING (deep lipid panel, CAC) your true risk dynamic whilst taking Rapamycin.
My point…this is an unresolved issue in human interventions.
The great pharma statin card trick.
-----100% CONCUR-----
**[quote=“MAC, post:277, topic:1434, full:true”]
The great pharma statin card trick.
[/quote]
It’s only a trick if the absolute risk is tiny to begin with. If the absolute risk of a heart attack is 10%, that’s 1 in 10, not 1 in a million, so a 25% risk reduction is highly significant in my book.
You make some good points. There are many studies showing cancer risk reduction with rapamycin, even in humans immunosuppressed after renal transplantation.
Mice are very cancer prone and most of the cancers you mentioned we never see, or even heard of in some instances.
I’m more concerned about cardiovascular risk. That’s less certain in my mind. There are certainly arguments to be made for various protective rapamycin mechanisms, such as reduction in foam cell formation, intimal smooth muscle proliferation , and endothelial function.
Was the doubling of CAD in mice or renal transplant patients?
Do mice live long enough to get CAD or die of cancer before that happens?
I believe I saw a study where more renal transplant patients got cardiovascular disease on rapamycin c/ w cyclosporine. Of course renal patients have all kinds of comorbidities so it’s difficult.
I’m honestly not certain about rapamycin and cardiovascular risk and I can’t see having such certainty until I see a good study on intermittent use in humans.
Some proliferation reduction yes, but in general, Rapamycin wasn’t this “great” cancer therapeutic. Seems the cancer community has moved on to other therapeutics.
The chart I posted was the wild type mice/Rapamycin study, cause of death. Doubling rate of CAD vs control mice.
Cancer is by far the highest % cause of death, 90+%, but there is some CAD. But seems vs humans, cancer is far more prevalent than CAD.
Neither am I. Dr B is a great “benevolent” Rapamycin champion, but there is NO data in humans to confirm. Might never see a well done RCT at the kinds of doses we’re experimenting with. So I have to say, we’re all n=1, forge your own risk pathway.
Lymphona is 50% higher in Rapamycin mice vs control. Yes, some of these are more rare in humans, but look at PULMONARY TUMOUR…almost double in Rapamycin mice, and one of THE top cancers in humans!
Even Blagosklonny isn’t claiming rapamycin as a great cancer therapeutic, he stresses that the evidence is for prevention.
Even in smokers it decreases the risk of lung cancer. There are researchers who critically claim that it Only reduces Cancer risk and that explains its longevity. Blagosklonny responded to that as well.
Renal patients on rapamycin are immunosuppressed and this clouds all studies in this group.
Atherosclerosis takes decades to develop and do its damage so we’re not going to know for sure. I’ll take a look at the mouse study and see what the absolute numbers were in the CAD group c/ w control.
