Yes, probably not a bad idea to just stick with sirolimus for now. Its only one research study, and no full lifespan studies have been done with everolimus, but it seems that sirolimus is a slightly lower risk approach than everolimus. If I already had everolimus I would still take it, but I’m a little less enthusiastic about everolimus now that I’ve seen that data.
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The following is quoted from FrankT.Hippo posted in LongeCity forum 2020:
I haven’t been following this threat for a while, but I wanted to give an update in case anyone was interested in this data point:
I have a poorly characterized mitochondrial disorder (“disorder of mitochondrial respiratory chain complexes”). I was in bad shape in January 2017 when I came across this thread and came into contact with Jaris.
Soon after, I started low doses of rapamycin. My condition has since stabilized and I am substantially more functional.
I was even able to travel a bit, something I have not been able to do for a decade.
I was taking Sirolimus prior, however that had terrible side effects. I have since switched over to Everolimus*, which I find much more tolerable.
Of note, I have had to increase doses to achieve the same effect, but I am still at relatively low doses (5 mg / once every three weeks).
I am going to try to boost the dose up to 10mg. I will let you know how that works.
*Note, Everolimus is Glenmark brand from India.Moreover, for whatever reason, I can tolerate the Everolimus much better. With sirolimus I am usually bedridden for a week while dosing: no energy, flu-like, weak, headaches, etc…-- but then I recover and in the following couple of weeks I feel improved relative to my baseline. I would compare the feeling to what I imagine chemotherapy to feel like. However, I will look into it.
Dec 2021-----------------------------------------------------------------------------------------------------
I have been following this thread for several years and have been taking rapamycin too.
I have a clinically diagnosed mitochondrial defect – seemingly due to a PINK1 and OPA1 mutation – which is disabling.
Sirolimus was a miracle drug for about 3 years – i was super productive with my behavioral genetics research – but the efficacy dissipated.
It is really hard to modify these conditions; nothing has panned out and my Harvard trained biomedical geneticist was somewhat black-pilled last I talked to her. So, I have realistic expectations. And in light of those, rapamycin was a stellar success.
I tried Everolimus but as predicted by those on this forum that did nothing.
I still take Sirolimus on and off but is has less potency – maybe the condition has just advanced — so I have moved on to trying other drugs including Semax, dihexa, and similar peptides to upregulate BDNF.
I am now procuring an order of SKQ1 a newly developed mitochondrial targeted anti-oxidant – since I had good experiences with MitoQ and CoQ10. And I am also experimenting with intravenous glutathione.
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Oh I can imagine the shorter half-life to be super useful at least when it comes to exercise training and performance.
I also sometimes wonder (based only on subjective feeling) if most of the benefits of rapa are in the first day or two, and rest of time is spent on waiting for it to wash out. If that is the case, then everolimus maybe a better candidate.
High doses may also come with less side-effects if there’s a shorter half-life. It’d be somewhat of a hit and run strategy then.
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Another potential advantage that comes to mind is that oral everolimus may have different tissue specificity when compared with rapamycin. In this scenario, alternating between the two every few months (or maybe combining them) may be a good strategy to distribute the benefits throughout the body.
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hello, could you please tell me what brand of Everolimus did you used?
Hi Lui, welcome to the forum and thanks for posting.
I’m thinking of adding everolimus the next time I order my rapamycin. Here are some quotes I got - see this post.
Also - I’ve recently added a list of the generic manufacturers of everolimus on this page listing all the companies offering everolimus generic medications.
its called Evermil 5mg, made by Glenmark of an Indian pharmacy
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thank you very much!
@RapAdmin I recall you are trialing Everolimus? Have you noticed any difference to Rapamycin?
As @shc states above it certainly makes sense intuitively.
Not yet. I plan to order it in the coming month.
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i bought 20 pills from NIBA healthcare of India. One pill costs $7.
try 5mg Everolimus yesterday with grapefruit juice, no side effect, feels good like the first time i took sirolimus months ago. I will try more times.
according to research papers, Klawitter 2015,
“One of the key differences between sirolimus and everolimus in these studies was that at therapeutically relevant concentrations everolimus, but not sirolimus, could distribute into brain mitochondria”. On the other hand, it said “everolimus is markedly more potent than sirolimus in inhibiting mTORC2 formation”.
Looks like it has both positive and negative effects. May be you just need only few mg of everolimus to reach the brain, you dont need 20 mg of sirolimus to cross BBB.
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Yes, interesting conclusions in that paper. I think most of the community still believe MTor2 inhibition leads to greater side effects?
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From the Klawitter paper:
“There is also evidence that everolimus alone, but not sirolimus, stimulates mitochondrial oxidation. In rat brain slices, in contrast to sirolimus which reduced high-energy metabolism, everolimus stimulated high-energy metabolism as indicated by significantly higher phosphocreatine and NAD/NADH concentrations.”
I’m not sure stimulating high-energy metabolism is a good thing for anti-aging effects.
We need lifespan studies with everolimus.
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Posted elsewhere, albeit transgenic EGFR mice. 85% lifespan increase…MASSIVE!
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Interesting… yes we need lifespan studies with Everolimus.
Mitochondrial oxidation sounds negative…
but…
higher phosphocreatine and NAD/NADH concentrations seems like it could be positive:
but I need to dig down much deeper into NAD/NADH ratios and the whole issue of correlation vs. causation to better understand this issue:
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Yes, not clear which is positive, and which is negative.
My view is that biochemical pathways are generally too complicated to base predictions on (this is esp. true for massively complicated pathways like NAD-related pathways).
So theory-less empirical evidence is always what I prefer. We have that (albeit mostly in mice) with rapamycin, so I’m inclined to stick with rapamycin.
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Actually some of the side effects from 20 mg dosing are a bit concerning like thrombocytopenia and neutropenia.
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Clinical remission of an inoperable malignant insulinoma by the combination treatment with octreotide and everolimus (2018)
This is an n=1 patient with existing cancer, treated with Everolimus 10mg/day, albeit dual drug intervention.
Abstract
"We report a 52-year-old woman with inoperable malignant insulinoma with multiple liver metastases. Histological examination of biopsy specimens from the pancreatic and hepatic lesions revealed pancreatic neuroendocrine tumor (pNET), G2. The tumor cells were positive for somatostatin receptor (SSTR) 2, 5, and the mammalian target of rapamycin (mTOR). Monthly intramuscular administration of octreotide LAR and once-daily oral administration of everolimus combination treatment markedly reduced the sizes of liver metastases, and hypoglycemia was
well controlled. Combination treatment with somatostatin analog and mTOR inhibitor may be another effective approach in inoperable metastatic malignant insulinoma.
After 20 months of combination treatment with octreotide and everolimus, all of the metastatic lesions of the liver were reduced in size, and many of those had disappeared. In addition, swollen lymph nodes around the pancreatic tumor had also disappeared."
20+ months at 10mg/day Everolimus, that is a high and long dosing exposure, likely high plasma and AUC levels. No data was reported of any side effects concerns.
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From the paper: Clinical remission of an inoperable malignant insulinoma by the combination treatment with octreotide and everolimus (2018)
Recently, everolimus, an orally active mammalian target of rapamycin (mTOR) inhibitor, has been shown to have antitumor growth effects in patients with pNET.3 The protein of mTOR is a serine/threonine kinase that regulates cell growth, proliferation, and metabolism. In pNETs, the expression of mTOR protein is upregulated.9 The expression and activity of mTOR and its downstream targets such as 4EBP1, S6, and eIF4E are strongly dependent on enhanced proliferative capacity and metastatic sta- tus in gastroenteropancreatic neuroendocrine foregut and mid- gut tumors. Evidence from preclinical studies suggests that the combination of pasireotide and everolimus may be synergistic by dual inhibition of insulin-like growth factor-1 (IGF-1) and mTOR signaling.10 The combination treatment may be more effective than each treatment. The maintenance therapy with somatostatin analog and mTOR inhibitor combination treatment may play a significant role in tumor control in patients with advanced NET, unless hyperglycemia induced. Further studies in larger numbers of insulinoma patients are required to support this suggestion.
4 | CONCLUSION
We reported a case of inoperable metastatic malignant insulinoma, in which liver metastases were markedly reduced and hypoglyce- mia was well controlled by monthly intramuscular administration of octreotide LAR and once-daily oral administration of everolimus. Combination treatment with somatostatin analog and mTOR inhibi- tor may be another effective approach in inoperable metastatic malignant insulinoma.