Rapamycin and risk of cardiovascular disease

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#704

We actually do NOT know that blunting spikes and reducing glucose AUC does not reduce incident CVD risk. I believe you are referencing only the ITP. It dosen’t do CAC scans on euthanized mice, only pathological post mortems of lesions.

But glucose is highly implicated in CVD due to it’s damage to the endothelial glycolyax and inflammation. Whether it’s spikes and/or AUC, it’s seems to be a causative progressing agent, in humans and wild type mice. A correlation between diabetes, metabolic syndrome and the #1 cause of death, CVD?

The Diabetes Mellitus–Atherosclerosis Connection: The Role of Lipid and Glucose Metabolism and Chronic Inflammation

“We also discuss the established pathophysiological features that link atherosclerosis and diabetes mellitus, such as oxidative stress, altered protein kinase signaling, and the role of certain miRNA and epigenetic modifications.”

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Repetitive Glucose Spikes Accelerate Atherosclerotic Lesion Formation in C57BL/6 Mice

A study using wild type mice, similar to ITP:

Conclusions

“These results indicate that glucose spikes can accelerate atherosclerotic lesion formation, with little influence on other metabolic disorders. Repetitive glucose administration in wild-type mice may serve as a simple and useful approach to better understanding the causal role of glycemic spikes in the development of atherosclerosis.”

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I take strong exception to their concluding remark “These results indicate that glucose spikes can accelerate atherosclerotic lesion formation, with little influence on other metabolic disorders”.

The ITP mice on glucose lowering meds live longer by delaying cancer…not an mTOR pathway, so I would suggest a pro-carcinogenic pathway is also implicated (cancer is 2nd leading cause of death in the US).

Canagliflozin extends life span in genetically heterogeneous male but not female mice
https://insight.jci.org/articles/view/140019

“Since most UM-HET3 mice die of neoplastic disease, the effects of Cana on cancer may be particularly relevant for its ability to extend mouse life span. In preclinical studies, Cana administered at high doses to rats increased the frequency of adrenal and renal tubular tumors, and induced Leydig cell hyperplasia and adenomas at all doses in male mice”

Association between haemoglobin A1c and all-cause and cause-specifc mortality in middle-aged and older Koreans: a prospective cohort study (2022, 16 yr followup, n=9294)

“Conclusions: We found U-shaped associations between HbA1c levels at baseline and over time and all-cause mortality in middle-aged and older Koreans. Additionally, the risk of cancer mortality increased both in low and high HbA1c groups, but CVD mortality increased only in high HbA1c group. In particular, people with liver diseases and low HbA1c levels had a high risk of all-cause mortality. Therefore, more careful management of these groups is suggested to identify any deteriorating health conditions.” (love the little reverse confounder comment on the low end curve…these people are sick, so unless you dabble into preemptive hypoglycemic risks, the lower the better)

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Look at the slope of the A1C/cancer graph.

Crushing glucose (keto/OMAD) is a central part of my biohacking stack. My A1c has been 5.0 for years, and my diet precludes spikes. Donating 450mL of blood every 8 weeks also dumps a lot of old gylcated and misfolded proteome junk.

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#705

So…back to rapamycin and CVD, the topic of this thread.

Is rising glucose on rapamycin BENEVOLENT??

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#706

I found your cited Korean study on HbA1C to be extremely interesting. I don’t buy that lower levels are a risk, that seems to be obvious reverse causation, but if you look at total mortality, the thing that really counts, the risk is significant over 6.
My guess is that most of us haven’t gotten over 6 with rapamycin. Blagosklonny clearly views it as benign regardless and he makes some good arguments.
There’s good evidence that rapamycin protects against all end organ damage from diabetes, and that’s very significant.

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#707

What is your reasoning for low carb? I find generally high carb low protein is what consistently worked both in mice and Okinawans.

#708

mTORC2 has a ton of downstream effects that overlap with mTORC1. Probably to be on the side of caution - probably do not want to play everolimus until there is more data on mTORC2, sticking to rapamycin seems cleaner since there are way too many overlapping effects. I really don’t get why Dr. Matt K said they were both equivalents - I wonder if he has ever changed his mind since then.

And I’m not sure why mTORC2 is considered inherently “bad” in the context of aging, since I see it as likely mixed effects.

But then again, AFAIK no ATP-competitive inhibitor studies done for aging can clarify that for me.

Appears that Dr. Matt K feels the same way here about the lack of studies on other classes of mTOR inhibitors (4:00):

#709

FWIW

This was posted back on June 21, 2022

The book on TOR

#710

I’d say that TOR 2 is the issue with everolimus. In theory , it’s the inhibition of TOR 2 from daily rapamycin usage that leads to immunosuppression in renal transplant patients. However, weekly use of everolimus at 5 mg quite clearly improved immune response by 20%.
Once again, the key is dosing and dosing intervals. You can argue that the longevity studies are done with rapamycin, but it can also be argued that the most significant study in humans and immune response was done with everolimus.

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#711

I think that’s a strong argument tong, and not just Okinawan’s but all long lived cultures are high carb, but of course not high refined carb.

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#712

It may be a more accurate statement is “medium carb” - right now I follow mostly fresh vegetables (e.g. spinach salads), nuts, fish (mostly salmon and sardines) and some fruit (mostly berries with yogurt, etc.), Keto granola, and minimize simple carbs, breads, pastas, etc. Reasoning is easy to keep a moderate calorie intake, fewer blood glucose spikes, more nutrient rich foods…

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#713

In a way yes.

Of note, a curiosity is the staple purple sweet potato has a lot of simple sugars in it namely sucrose (1/2 fructose and 1/2 glucose). Although it’s “natural sugar”, if we counted “natural sugar” similar to “added sugar”, it’s actually more than what the AHA recommends as maximum amount of added sugars for adults - if you calculate how much sugar is in just the sweet potatoes alone that they eat per day.

Re: @RapAdmin basically this is jam packed with simple carbs actually!

I believe this can be explained by compounds that act similarly to acarbose in the staple - based on the processes that Okinawans use that alter the chemistry in it.

#714

The purple sweet potato is a nutrient giant and loaded with anthocyanins.

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#715

Yes it is.

#716

Yep yep. Might I add the anthocyanins in purple sweet potato are much more cost effective than supplements and blueberries :wink:

#717

Is that actually purple yam? Not familiar with that one - but beware of confusion. Also, processing may change a lot - leading to possibly different results.

#718

The package states organic purple sweet potato powder, the ad copy states pure natural premium purple yam powder.

#719

Yep unfortunately the industry uses yam and sweet potatoes interchangeably.

#720

I posted briefly here.

Basically, as we age, all of us will have a decline cerebral metabolic rate of glucose use, which is symptomatic with neurodegeneration. Being diabetic massively accelerates this curve.

As a way to ameliorate this loss, generating ketones via diet offer mitochondria an alternate fuel source to promote optimal function. Neurons, Astrocytes and Oligodendrocytes all metabolise ketone bodies

Ketones have all sorts of other pro-longevity signalling pathways.

The diet combined with fasting, of course, blunts glucose spike/AUC, already shown to promote longevity in mice, so that’s an additional freebie.

A ketogenic diet extends longevity and healthspan in adult mice

And by default, a ketogenic diet imposes protein restrictions, and we know quite conclusively in plethora of rodent studies, that protein restriction, most especially BCAA, and furthermore, leucine restriction promotes longevity.

Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice

Metabolomics Study of Isocaloric Different Dietary Patterns on the Life Span in Healthy Population

Promoting Health and Longevity through Diet: From Model Organisms to Humans
https://www.cell.com/action/showPdf?pii=S0092-8674(15)00186-5

Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health

“We have determined that reduced dietary BCAAs improves metabolic health even in the absence of significant alterations in the dietary carbohydrate:protein ratio”

Daily caloric restriction limits tumor growth more effectively than caloric cycling regardless of dietary composition

Caloric Restriction vs. Animal-Protein Restriction

“The lifespan extension associated with dietary restriction may be due less to a reduction in calories, and more to a reduction in animal protein (particularly the amino acid leucine, which may accelerate aging via the enzyme TOR).”

As for Okinawans/Sardinans, the long lived “islander” cohorts (yet vastly different diets), from all the literature I’ve read, their longevity signal is majority genetic (enriched lineages), but on the specific dietary side, what they do share in common and is pro longevity is…LOW animal protein and mild CR. This would be very consistent with all the rodent longevity literature.

New Horizons: Dietary protein, ageing and the Okinawan ratio

“Such studies in insects and mice indicate that animals with ad libitum access to low-protein, high-carbohydrate diets have longest lifespans. Remarkably, the optimum content and ratio of dietary protein to carbohydrates for ageing in experimental animals are almost identical to those in the traditional diets of the long-lived people on the island of Okinawa. The energy from their diets was derived from 9% protein and 85% carbohydrates”

Healthy aging diets other than the Mediterranean: A Focus on the Okinawan Diet

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So being low carb/ketogenic and overlaying OMAD fasting, I get a combination of benefits and hedges, all associated with longevity:

  1. Low glucose spikes/AUC.
  2. Low animal protein (classic ket macros 20% protein, 75% plant fats, < 5% net carbs)
  3. Ketone bodies generation as alternate compensatory brain fuel for aging, lowers inflammation (NLRP3 inflammasome), HDAC inhibitor, lowers body fat, preserves muscle loss.
  4. Fasting and all the metabolic benefits, lowering fT3 and metabolic rate. Ghrelin spurs brain neurogenesis.

I feel amazing after 6 yrs on the switch, much leaner, no impediments to muscle build, excellent biomarkers. I have super high energy level. My wife tells me my memory and cognitive is amazing.

But a long way to go to a 100…the hill will only get steeper.

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#721

I’ll add Okinawans + Westernization = about average Japanese life expectancy, thus not sure much is genetics

They already naturally blocked glucose spikes and relatively low protein.

I’ll also add traditionally Okinawans tend to skip dinner. That’s very close to TRF/Ketones when it adds up to 16 hours - especially for lean folks. :slight_smile:

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#722

The Okinawan diet is amazing, super nutrient dense!

I am simply trying to translate the known longevity literature into a human protocol. I do eat a ton of nutrient dense whole foods ONLY, whether wild animal protein, plant fats, or above ground vegetables.

I tell anyone to just start with dumping sugar, simple carbs, and fasting…they confer huge metabolic benefits without doing a full diet reboot.

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#723

Oh and btw I’d be careful with Greger at “NutritionFacts” he can get misleading. The previous name of “NutritionFacts” was “Vegan Research Institute” and he used to promote veganism as a cure for death.

He almost certainly reads “animal meat = bad” with cherry picking. Not saying all the cherries he picks are bad - but I would simply be wary of bias. If one is a pragmatic vegetarian - I don’t have any issues. But he is almost certainly of the ideological type.

Leucine I don’t think is particularly “bad” if you are already doing CR and rapa. There’s also mTOR tissue-specificity in liver, fat, and muscle for leucine while barely staying long enough in your system with an ultra-short half-life. I’m not eating tons of animal meat or taking BCAA supplements to sip Leucine all day (maybe will in very specific situations in the future), but I’ll happily eat some salmon roe and an egg after a workout.

“Preventing hyperphagia by calorie restriction or pair-feeding averts the health costs of a high-BCAA diet.”

https://www.nature.com/articles/s42255-019-0059-2

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