I want to do a clean trial separating the two. I want to know if Everolimus alone can give me a better trade off. I’ve seen enough people on this forum running up the hill then backing off.
I am still working on Rapamycin!
And people much smarter than me would have mixed sirolimus and Everolimus in clinical trials if a benefit was perceived, vs Everolimus only.
I doubt that, given the patented status until recently. And now that its off-patent, I wonder if anyone would fund the studies given the similarity of the compounds.
I am referring to human clinical trials last 10yrs. There was a switch to Everolimus from Rapamycin from a pharmacological and efficacy reasons.
Just had tests last week. Didn’t take the ApoB test, but I will in the future.
Oddly, I have different ratios than your, maybe diet or supplements?
I had stopped taking metformin and empflagaflozin for about 2 months before the latest test.
My lipids were under complete control using diet, exercise, and once-a-day metformin.
I was going to drop empagliflozin anyways because it seemed to have little effect on my blood lipids. Metformin has always worked extremely well for me and I have never had any subjective or measurable negative side effects.
I am going on metformin again and will retest in about 60 days.
So rapamycin has this long half life of about 2.5 days. Maybe that’s something we want. Maybe we want it hanging around for awhile.
On the other hand, everolimus has a half life of only about 1 day. It peaks and gone. Fewer side effects.
So now I’m on 6 mg per week. I could go up to 4 mg’s each for a total of 8 per week. Best of both worlds IMO.
The key benefit of empagliflozin its that it blunts the blood glucose spikes that seem to cause accelerated aging: Canagliflozin - Another Top Anti-aging Drug
Are you saying it did not do that for you? You still saw significant postprandial spikes in BG measures?
Can’t really address that issue. My main goal was to keep my morning fasting glucose as low as possible. I really don’t eat that many carbs anymore except for the occasional spaghetti dinner. I have been monitoring my glucose spikes after what I consider to be a high-carb dinner and rarely have recorded spikes above 150, so for me I don’t worry about it. It is tough to keep my supplement/medication stack at a reasonable level, so sometimes I drop a supplement, not because it isn’t good, but because I have replaced it with something that I deem is better for me. Supplement in supplement out is my motto for keeping them at a reasonable number, but I am not sure I have achieved that goal yet.
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.”
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.”
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)
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.
So…back to rapamycin and CVD, the topic of this thread.
Is rising glucose on rapamycin BENEVOLENT??
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.
What is your reasoning for low carb? I find generally high carb low protein is what consistently worked both in mice and Okinawans.
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):
FWIW
This was posted back on June 21, 2022
The book on TOR
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.
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.
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…
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.
The purple sweet potato is a nutrient giant and loaded with anthocyanins.
Yes it is.
Yep yep. Might I add the anthocyanins in purple sweet potato are much more cost effective than supplements and blueberries 
