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I am on my second week of Rapamycin. I can't describe any further, as it will not be helpful in this early stage. I have quick viral onset CFS with classic symptoms, Tri-Guy.
Have any of you guys who have access to Rapamycin tried combining it with Arginine (several-gram doses/day)?
Arginine is a substrate first and I'd expect Rap to divert its metabolism, and the biggest change would be in macrophages.What would be the benefit of adding the arginine? It activates mtor doesn't it? While Rapamycin inhibits it.
“Sirolimus (INN/USAN), also known as rapamycin, is a macrolide compound” [wikipedia]
We know the general characteristic of macrolides.. favorable shifts in the microbiome [post] and this family is also used by MDs Jadin and Botelo in their protocols for CFS and other related conditions. As with strains with probiotics, each member of a antibiotic family has it’s own characteristics.
Sirolimus is well studies (18K articles on pubmed)
- “a large number of small molecules such as farnesol, fatty acids, rapamycin, geldanamycin, histone deacetylase inhibitors, and cell cycle inhibitors have been reported to modulate the yeast-to-hypha transition in C. albicans.” [2011, Full Text]
- “Rapamycin, a hydrophobic macrolide produced as a secondary metabolite by the soil bacterium Streptomyces hygroscopicus, was initially discovered as an antifungal agent against C. albicans (139).”
- “Rapamycin markedly prolonged lifespan and health span in cancer- and infection-prone mice supporting disease mitigation as a mechanism for mTOR suppression-mediated longevity extension. It modestly altered gut metagenomes,” [2015]
- ” Four operational taxonomic units were significantly modulated in eRapa mice, belonging to Firmicutes, Acidobacteria, and Bacteroidetes”
- Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice [2016].
- Chronic Repression of mTOR Complex 2 Induces Changes in the Gut Microbiotaof Diet-induced Obese Mice[2016]. [Full Text]
- ” the abundance of unclassified Marinilabiliaceae and Turicibacterdecreased in response to .. rapamycin (mTOR).”
- “Mechanistic target of rapamycin (mTOR) is a central regulator of energy storage and consumption, and is implicated in deleterious states such as cancer, metabolic diseases and ageing17. Because over-activation of mTOR complex 1 (mTORC1) signaling by excessive energy intake plays a crucial role in metabolic disorders17,”
- “rapamycin changed the relative abundances of Turicibacter, unclassified Marinilabiliaceae, Alloprevotella, unclassified Porphyromonadaceae, Ruminococcus, Bifidobacterium, Marvinbryantia, Ruminococcus (Lachnospiraceae), Helicobacter, and Coprobacillus to those observed in HFD-fed mice”
I am discontinuing the rapamycin after 14 days; ultimately, it was not the panacea that was described earlier and I did not expect it to be.
Is this your first time trailing an immunosuppressant?
Rapamycin, an inhibitor of the mTOR pathway, can extend lifespan and improve age-related functional decline in mice, thereby providing the first proof of principal that a pharmaceutical agent can slow the aging process in mammals
Part of the challenge in addressing the potential of rapamycin (or its analogs) as a pro-longevity therapeutic lies in its known clinical risks for adverse side-effects. Primary amongst these are metabolic defects that include hyperglycemia, hyperlipidemia, insulin resistance and increased incidence of new-onset type 2 diabetes.
Several recent studies have elegantly shown that chronic treatment with rapamycin inhibits mTORC2 signaling which may be a primary culprit in its alteration of glucose metabolism.
However, the study quoted below found the effects on glucose metabolism were only partially reversible on rapamycin discontinuation.However, once we ended the rapamycin treatment, all markers of glucose homeostasis almost completely returned to normal; i.e., glucose homeostasis in previously rapamycin-treated mice was no different from those never treated with rapamycin. Perhaps most interestingly, this reversal occurred in a relatively short period of time (1-2 weeks) even after long term (4 months) rapamycin treatment, suggesting that these metabolic side effects are a consequence of ongoing use of this drug and are not permanent alterations to the glucose homeostatic network.
Current evidence indicates that the mammalian target of rapamycin inhibitor rapamycin both increases longevity and, seemingly contradictorily, impairs glucose homeostasis.
So male mice given rapamycin are at risk from diabetes, but female mice are not at risk.We observed that treatment with rapamycin for 52 wk induced diabetes in male mice, characterized by hyperglycemia, significant urine glucose levels, and severe glucose and pyruvate intolerance. Glucose intolerance occurred in male mice by 4 wk on rapamycin and could be only partially reversed with cessation of rapamycin treatment. Female mice developed moderate glucose intolerance over 1 yr of rapamycin treatment, but not diabetes.
The study examining the effects of intermittent rapamycin is this one. It says that:One possibility could be intermittent treatment with rapamycin; Leontieva et al recently showed that a once-weekly treatment with rapamycin extends lifespan in high fat-fed mice without altering glucose or insulin levels
We recently identified an intermittent rapamycin treatment regimen-2mg/kg administered every 5 days-with a reduced impact on glucose homeostasis and the immune system as compared with chronic treatment
So intermittent rapamycin means taking a dose once every five days, rather than say daily. The mouse dosage of 2 mg/kg used corresponds to a human dose of 0.16 mg/kg, which for an 80 kg human would be an oral dose of 12.8 mg taken once every five days.intermittent rapamycin administration had minimal impact on glucose homeostasis in young mice ... These results sharply contrast with the impaired glucose tolerance observed during continuous administration of rapamycin to mice
mTORC2 is inhibited only by long-term, chronic treatment with rapamycin. Therefore, we hypothesized that intermittent treatment with rapamycin would more selectively target mTORC1 than mTORC2, and by doing so, reduce the negative effects of rapamycin while still extending lifespan.
NEFAs = nonesterified fatty acidsRapamycin’s inability to activate fatty acid β-oxidation and ketogenesis in mice could generate an imbalance resulting in the accumulation of NEFAs, which may play a role in the development of insulin resistance. Activation of fatty acid β-oxidation by either DR or metformin corrects this imbalance and might lead to improved insulin sensitivity in animals treated with rapamycin.
Rapamycin and Diabetes Risk
This is an interesting article to read:
The two faces of rapamycin – why a life-extending drug also increases risk of diabetes
The article says that the anti-aging and longevity effects of rapamycin (which increase mice lifespan by up to 14%), comes from this drug's inhibition of mTORC1.
But a downside of rapamycin comes from its effects on mTORC2, which results in a reduced ability to stabilize sugar levels in the blood, and the article says that people who take rapamycin for a long time become resistant to insulin, and intolerant to sugar.
This diabetes risk was also touched on earlier in this thread (see here).
[...]
I wonder though if rapamycin's effects on glucose and pyruvate metabolism (via its mTORC2 inhibition) could be the reason this drug improves ME/CFS symptoms?
If we look at some of the metabolic studies on ME/CFS, there appears to be an altered energy metabolism in ME/CFS, which involves the way glucose is processed in glycolysis (Ron Davis's theory) and/or the way pyruvate is processed in the mitochondria (Fluge and Mella's findings).
So could rapamycin's normally detrimental effects on glucose and pyruvate metabolism actually be beneficial in ME/CFS, and the reason why rapamycin improves ME/CFS symptoms?
I am not so concerened over long term side affects as I currently have very little quality of life.
Whether someone wants to risk the serious side effects of a drug is a personal decision, and usually best reached with the help of a willing doctor. However, it is important to make the risks clear in advance.
And if there are ways to reduce or avoid the risk of serious side effects, then that is very useful info. The concomitant use of metformin with rapamycin, and/or the intermittent rapamycin protocol, detailed above are possible ways to reduce the risk of developing diabetes from rapamycin.
Hip
After suffering from severe CFS for 36 years, attempting a miriad of treatments and mutiple long stay hospital and care home admissions, I have concluded that I now have no alternative but to trial rapamycin, cyclosporine, cyclophodpmide and rituximab, probably in this order.
I have come to the conclusion that there are currently only heavy duty drug options that are viable treatments for severe patients. If anything is going to give the illness a jolt, I feel that this must be drugs that have a major effect.
I am not so concerened over long term side affects as I currently have very little quality of life.
I am monitoring peoples progress on rapamycin with keen interest.