#2175

My intuition is also that it would be more than a few years, but that’s just a feeling. Do you have any data or paper suggesting the 100 yrs or so?

#2176

Perhaps the issue is the different half-lives of rapamycin vs. everolimus, combined with the typically higher doses that many of us are using here (vs. the Mannick study). Everolimus has a half life that is about 50% less than rapamycin, and the people seeing higher lipid levels here are, I think, typically using dosing above the 8mg/week level.

With the higher dosing, and longer half-life, I would expect the AUC (and blood/sirolimus trough levels) to be much higher in the Rapamycin-users here compared to the everolimus users in the Mannick study.

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#2177

Could perhaps partially be that the Mannick study was relatively short (weeks) and a lot of people here have been dosing rapa over longer windows (many months, years)

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#2178

Maybe the the reason is that hyperlipidemia occurs in around 80% of kidney transplant patients (I did not go in depth of it) but seems that this is independent of the drug used. In cancer patients on high dose sirolimus therapy hyperlipidemia/dyslipidemia occurs in about one third of the patients.
I believe hyperglycemia is a worse problem of rapamycin.

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#2179

This intuition doesn’t pan out when mathematically modeled because of Taeuber’s paradox: aging increases the risk of death from so many causes simultaneously and at an exponentially-increasing rate that there’s always another cause of death lurking just over the horizon if you beat back one cause of death in isolation. There is a famous paper by Jay Olshansky that illustrates this:

Eliminating all forms of cancer (22.45% of all deaths in the United States in 1985) would increase life expectancy at birth by 3.17 years for females and 3.2 years for females. Eliminating ischemic heart disease (25.73% of all deaths in 1985) would increase life expectancy at birth by 3.0 years for females and 3.55 years for males. Eliminating both diseases together would increase life expectancy at birth by only 7.02 years for females and 8.1 years for males. If mortality attributable to the combination of all circulatory diseases, diabetes, and cancer was eliminated (71.34% of all deaths in 1985), life expectancy at birth would increase by 15.82 years for females and 15.27 years for males.

The added years would be lower if calculated today, because we’ve subsequently lowered deaths from ASCVD substantially, so there’s less on the table. This is why direct anti-aging interventions would be so valuable.

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#2180

That doesn’t explain the hyperlipidemia in the Mannick study or in people on this forum, since no one in the former and only one person among the latter have kidney transplants.

(But maybe I misunderstood your point; I’m not perfectly clear what post you were responding to).

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#2181

Thanks for sharing. But that analysis does itself not take into account that the decease processes are connected in a correct way?

Eg if we really did cure all forms of diabetes, then the number of cancer deaths and the amount of obesity would NOT be constant, but that is what Olshansky paper’s framework assumes? Hence diabetes cures also less cancer deaths, but paper would not calculate those cancer deaths avoided?

Similarly if we cured all cardiovascular disease then vascular and probably also AD dementias would also go down and NOT be the same, but the paper’s simplified analysis framework again would hold dementia deaths constant?

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#2182

The geroscience hypothesis is that if you hit one of the aging pathways then you hit a lot or all of the age related diseases. This includes diabetes and cancer.

I think I have evidence (it not that much because it is mainly friends and family) that proves this hypothesis.

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#2183

Yes exactly, and it does not seem like the Olandsky paper mentioned above takes that into account.

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#2184

In a sense it substantiates it. The point is that if you sort things out at the core (which IMO is about gene expression/protein production) then it fixes all of these things.

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#2185

Cardiovascular disease is a time based disease.

Time * apoB count. If apoB is high enough, the onset of the disease will be so quickly that it nullifies the hypothesis that it is an age-related disease and will be reduced by a geroprotector.

Hence why everyone who don’t take care of it will be bottlenecked by ASCVD and die from it.

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#2186

CVD is also affected by differentiation difficulties.

Cellular senescence is a fundamental mechanism of various cardiovascular diseases. It is a stress or damage response that characterized by permanent proliferation arrest, tumor suppressor pathway activation, apoptosis resistance and special secretory phenotype in aged or diseased organisms

Senescent cells AIUI are at least in part and probably overwhelmingly those cells which have failed to differentiate (hence to be found where there is renewal). As people know I think that is mainly because of a shortage of nuclear acetyl-CoA which has a number of potential causes one of which is under expression of SLC25A1 another of which is inefficient mitochondria.

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#2187

Okay, but it doesn’t adress the atherogenesis from apoB particle concentration, as I said earlier, people who are young with high enough apoB throughout life develops ASCVD quickly. And any mechanistic speculation has to be confirmed with randomized controlled trials or genetic studies. It is very low quality evidence, on the bottom of the evidence pyramid.

Hierarchy-of-evidence-pyramid-The-pyramidal-shape-qualitatively-integrates-the-amount-of
Hierarchy-of-evidence-pyramid-The-pyramidal-shape-qualitatively-integrates-the-amount-of850×499 60.6 KB

It is common for engineers etc to overly rely on mechanistic data for their decision making.

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#2188

I think we can all agree that low ApoB and LDL is a good thing from the perspective of ASCVD. :slight_smile:

But maybe not completely…

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#2189

That’s too lukewarm. Extremely low apoB will most likely going to prevent the formation of atherosclerosis. Any other hypothesis, which are unproven and are speculation, are totally unnecessary as this captures everything.

People who aren’t targeting optimal apoB levels without giving sound reasons not based on mechanistic speculation or assosciation studies, are probably doing so because they’re stuck in an ideological flywheel IMO. They’ve built their ideas too much and the momentum is taking them places where they wouldn’t go otherwise if they took a breath, relaxed, and considered the evidence once more.

This is typically used to justify above optimal apoB levels. It’s probably a way to cope.

Of course if someone already has atherosclerosis, optimal apoB is not enough, inflammation for example is important as well.

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#2190

I have, however, assumed apoB is causative, but not necessarily the only cause. I do wish to keep my apoB in a good territory. Not all the labs measure it, but I am OK with the range I am getting.

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#2191

There is a benefit of lowering apoB much lower than normal levels based on randomized controlled trials showing a benefit in doing so.

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#2192

I’d love to lower my ApoB more. That’s why I’ve added ezetimibe. I’ll retest my levels after Christmas.

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#2193

The only consensus on LDL-C is that there is a weak but statistically significant correlation between LDLC and atherosclerosis. Which means that at a population level there is a weak correlation on average between the 2. There is no consensus about causation though.

Now, and especially on that forum, people are not an average but a N of 1 and at that level those correlation are not applicable

LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature

Introduction : For half a century, a high level of total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) has been considered to be the major cause of atherosclerosis and cardiovascular disease (CVD), and statin treatment has been widely promoted for cardiovascular prevention. However, there is an increasing understanding that the mechanisms are more complicated and that statin treatment, in particular when used as primary prevention, is of doubtful benefit.

People should get at least once their Lipoprotein (a) and an NMR lipid panel and stop obsessing about a weak biomarker.

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#2195

Maybe but people in the paper you linked has been stuck in their conflict of interest flywheel.
From the paper:

Conflict of interest: J.F.B. has received research grants from Regeneron and Ferring Pharmaceuticals and honoraria for consultancy from Novo Nordisk. C.J.B. has received honoraria for consultancy and lectures from Amgen and AOP Pharma. J.B. has received research grants from Amgen, AstraZeneca, NovoNordisk, Pfizer, and Regeneron/Sanofi and honoraria for consultancy and lectures from Amgen, AstraZeneca, Eli Lilly, Merck, Novo-Nordisk, Pfizer, and Regeneron/Sanofi. E.B. has received honoraria from AstraZeneca, Amgen, Genfit, MSD, Sanofi-Regeneron, Unilever, Danone, Aegerion, Chiesi, Rottapharm, Lilly, and Servier and research grants from Amgen, Danone, and Aegerion. A.L.C. has received grants from Pfizer, Sanofi, Regeneron, Merck, and Mediolanum; non-financial support from SigmaTau, Menarini, Kowa, Recordati, and Eli Lilly; and personal honoraria for lectures/speakers bureau or consultancy from AstraZeneca, Genzyme, Menarini, Kowa, Eli Lilly, Recordati, Pfizer, Sanofi, Mediolanum, Pfizer, Merck, Sanofi, Aegerion, and Amgen. M.J.C. has received grants from Amgen, Kowa Europe, and Pfizer; and personal honoraria for lectures/speaker’s bureau from Akcea, Alexion, Amarin, Amgen, AstraZeneca, Daiichi-Sankyo, Kowa Europe, Merck/MSD, Pfizer, Sanofi, Regeneron, and Unilever. M.J.D., L.L.D., G.P., M.-R.T., and B.v.d.S. have no conflict of interest to declare. S.F. discloses compensated consultant and advisory activities with Merck, Kowa, Sanofi, Amgen, Amarin, and Aegerion. B.A.F. has received research grants from Merck, Amgen, and Esperion Therapeutics; and received honoraria for lectures, consulting and/or advisory board membership from Merck, Amgen, Esperion, Ionis, and the American College of Cardiology. H.N.G. has received grants and personal honoraria for consultancy from Merck; grants from Sanofi-Regeneron, Amgen, and Medimmune/AstraZeneca; and personal honoraria for consultancy from Janssen, Sanofi, Regeneron, Kowa, Pfizer, and Resverlogix. I.G. has received speaker fees from MSD and Pfizer relating to cardiovascular risk estimation and lipid guidelines, and consultancy/speaker fee from Amgen. R.A.H. has received grants and personal honoraria for consultancy from Acasti and Akcea/Ionis; grants from Regeneron and Boston Heart Diagnostics; and personal honoraria for consultancy from Aegerion, Amgen, Gemphire, and Sanofi. J.D.H. reports honoraria for consultancy from Gilead, Pfizer, Regeneron, Sanofi Aventis, Merck, Gemphire, BioEnergenix, and stock options from Catabasis. R.M.K. has received research grants, consultancy honoraria, and non-financial support from Quest Diagnostics and is also co-inventor of a licensed patent for measurement of lipoprotein particles by ion mobility. U.L. has received honoraria for lectures and/or consulting from Amgen, Medicines Company, Astra Zeneca, Berlin Chemie, Bayer, Abbott, and Sanofi. U.L. has received honoraria for board membership, consultancy, and lectures from Amgen, MSD, Sanofi, and Servier. L.M. has received honoraria for consultancy and lectures from Amgen, Merck, Sanofi-Regeneron, Mylan, and Daiichi-Sankyo. S.J.N. has received research support from Amgen, AstraZeneca, Anthera, Cerenis, Novartis, Eli Lilly, Esperion, Resverlogix, Sanofi-Regeneron, InfraReDx, and LipoScience and is a consultant for Akcea, Amgen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Merck, Takeda, Pfizer, Roche, Sanofi-Regeneron, Kowa, and Novartis. B.G.N. reports consultancies and honoraria for lectures from AstraZeneca, Sanofi, Regeneron, Amgen, Akcea, Kowa, Novartis, Novo Nordisk. C.J.P. has received research support from MSD and honoraria from Sanofi/Regeneron, Amgen, and Daiichi-Sankyo. F.J.R. has received personal honoraria for consultancy and non-financial support from Amgen, Sanofi/Regeneron, and The Medicines Company. K.K.R. has received grants and personal honoraria for consultancy, advisory boards and/or lectures from Amgen, Sanofi, Regeneron, MSD, and Pfizer personal honoraria for consultancy, advisory boards and/or lectures from Abbvie, AstraZeneca, The Medicines Company, Resverlogix, Akcea, Boehringer Ingelheim, Novo Nordisk, Takeda, Kowa, Algorithm, Cipla, Cerenis, Dr Reddys, Lilly, Zuellig Pharma, Silence Theapeutics, and Bayer. H.S. has received research grants from AstraZeneca and honoraria for speaker fees/consultancy from AstraZeneca, MSD, Amgen, Bayer Vital GmbH, Boehringer Ingelheim, Novartis, Servier, Daiichi Sankyo, Brahms, Bristol-Myers Squibb, Medtronic, Sanofi Aventis, and Synlab. L.T. has received personal honoraria for lectures/speakers bureau or consultancy from MSD, Sanofi, AMGEN, Abbott, Mylan, Bayer, Actelion, Novartis, Astra, Recordati, Pfizer, Servier, and Novo Nordisk. She is also the President, European Atherosclerosis Society (EAS) and an Editorial Board Member, European Heart Journal. G.F.W. has received research support from Sanofi, Regeneron, Arrowhead and Amgen, and honoraria for board membership from Sanofi, Regeneron, Amgen, Kowa, and Gemphire. O.W. has received honoraria for lectures or consultancy from Sanofi and Amgen.

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