#159

Reading the second paper i see in vitro tests of rapamycin and everolimus, but it appears that only everolimus was tested in vivo. (The KpK group vs KeK) I am, however, using my phone whilst taking my son to a climbing lesson. Hence i am not sure i am right.

The first paper does not appear to test rapamycin.

#160

The first paper says:

mTORC1 inhibitors are approved for adjunctive treatment of TSC-refractory seizures [Citation16,Citation17]. Everolimus, which had previously been approved for treating TSC-associated SEGA and renal angiomyolipoma, was shown to reduce seizures in phase 3 EXIST-3 study and was subsequently approved for the treatment of refractory partial seizures in patients with TSC [Citation15–Citation17]. Sirolimus is another mTORC1 inhibitor that has been evaluated to treat multiple manifestations of TSC, similarly to everolimus [Citation3]. However, in an open-label crossover study evaluating sirolimus as add-on therapy in intractable TSC seizures (patients randomly assigned to treatment with of sirolimus either during the first or second period of 6 months over a 12-month study), sirolimus did not significantly reduce seizure frequency [Citation43] (Table 2). Because of the strong phase 3 data now available for everolimus for seizure reduction in TSC, and the lack of large-scale clinical data (and regulatory approval) for sirolimus, the authors currently recommend using the mTOR inhibitor that has the approved indication, particularly if the indication has made the drug easier to obtain due to insurance issues or cost. Pharmacologically, these drugs have the same effect of inhibiting mTORC1; however, they differ in terms of lipid solubility, half-life, and metabolism [Citation3]. In clinical practice we have found that some patients can be switched from one mTOR inhibitor to the other if necessary due to adverse effects or lack of efficacy; in some cases, this may also lead to improvement.

I didn’t notice the last bit when I first read the paper. The individual variability is very interesting :thinking:

1 Like
#161

That is in another paper. When i am back home i need to revert to working on my main company’s accounts and dont have time to spend chasing down references.

I agree it is sensible over time to see what can be done to improve on rapamycin. But it is not on my priority list at the moment.

Everolimus may be better than rapamycin for some purposes. OTOH I now have my CGM running and intend first trying a chunky dose of UA. Then depending on the situation i want to take another dose of rapamycin ideally with still a relatively high level of mk7.

#162

I think you make good points but I think it is important not to overstate them.

The answer to your first point could be as simple as dose. Everolimus is apparently more bioavailable so its serum levels may be higher in studies comparing effect on seizures and neuroinflamation on a mg for mg basis. It’s also often dosed differently due to its shorter T 1/2.

The answer could also be similar to the debate on why canagliflozin might increase longevity and empagliflozin might not. We don’t really know because we don’t know the precise mechanism and we don’t know what is important for the longevity component. I was simply stating that it is not clear that everolimus’ mechanism of action in seizure treatment proceeds through MTOR inhibition. It might even be through systemic changes that do permeate the BBB.

Your final point about the FDA and clinical practice I think comes from the fact that Everolimus has been pushed in studies because of a profit motive. Papers are published and data spun to suggest that it is a vast improvement over Rapa but as I said they usually don’t include Rapa as a control but rather site historical data about Rapa’s side effects and claim that the same effects were not seen in their study. Nobody is doing this for Rapa because the patent has long run out and it is cheap and easy to produce. I appreciate the studies you sited that actually do make direct rapa comparisons.

Everolimus also has an IV protocol so it is easy to dose for these studies without worrying about bio-availability from the gut.

1 Like
#163

The other point that doesn’t make sense to me is that the molecular modifications to rapa to produce everolimus make it more water soluble and more polar… This would seem to reduce it’s ability to cross the BBB and engage brain MTOR.

To produce everolimus, a modification is made to the C40 position of the rapamycin molecule by adding a hydroxyethyl group, essentially creating a hydroxyethyl ether derivative of rapamycin, which significantly improves its pharmacokinetic properties compared to the original rapamycin molecule; this change allows for better oral bioavailability and absorption in the body

1 Like
#164

To Desertshores’s point, and against those that argue from the lower number of longevity-relevant studies in Everolimus: AFAIK, the only animal study showing preserved muscle in aging rodents from a rapalog used Everolimus, not rapa.

No, but it’s been done by weight in other longevity studies (though I doubt individualized to the specific mouse); also, in ITP they dosed in in ppm of food, so the larger a mouse was (and thus the more it ate) the higher its rapa dose would be.

True, but as I pointed out here,

#165

Side note: Empagliflozin extends lifespan in rodents (based on one paper). And we know one mechanism as Mendelian randomization shows that SGLT2 inhibition extends male lifespan.

Yes the financial incentives are not in favor of rapa. But side by side comparisons seem to show superiority of everolimus in some brain conditions: Everolimus is better than rapamycin in attenuating neuroinflammation in kainic acid-induced seizures 2017 (same paper)

How do we explain that other than the dose?

2 Likes
#166

In the in vitro tests as I remember it they used 1 nano Molar both E and R/S. Normally people use a higher Rapamycin dose. Hence to do the comparison properly would require a higher dose. E actually has a higher molecular mass.

#167

Sorry for not getting back, my practice has become busy.

So my thoughts would be still intermittent with this, 30 hr T1/2, but that is with daily dosing, I suspect it’ll be shorter, like rapamycin with a single big dose cyclically.

Levels are harder to get and cost more than sirolimus.

Cost of the meds, at CVS 60 x 0.75 mg are $172. It looks like equivalent potency is 0.75 mg everolimus = 1 mg of sirolimus.

My tendency would be to do a mg for mg or higher substitution with everolimus, maybe even 1.25 mg of everolimus to one’s prior 1 mg of rapamycin. E.g. if taking 8 mg of Rapamycin q7 days, I’d look at 10 mg of everolimus q7 days to account for #1 higher potency or everolimus, but then shorter half life so the time in a therapeutic level will be similar, but your peak with the everolimus would be higher by quite a bit.

These are just my thoughts on it - anyone acting on anything should consult their doctor.

3 Likes
#168

I had not heard that Empagliflozin had been tested for longevity in mice. That’s good news if it also showed increase in health/life span. I’d also not seen the Mendelian randomization. I wouldn’t have thought SGLT2’s had been around long enough to power a MR study… Can you link both of these? I usually follow the mega thread on SGLT2’s pretty closely but I must have missed this interesting bit.

re rapa vs Everolim paper in kainic acid seizures

Perhaps we are having this discussion prematurely? I mean it’s one paper from a Chinese group, experiments performed in vitro and in mice, and its an induced seizure with questionable human clinical relevance. I’m just not sure it’s worth our time yet.

#169

Yes, in males only (same as canagliflozin):

Yes but they’re smart and looked at the father’s age (what a coincidence, same as the ITP and the above paper!): Canagliflozin - Another Top Longevity Drug - #1067 by adssx

2 Likes
#170

Answer from Jose-Alberto Palma MD PhD FAAN who led the failed trial of sirolimus in MSA:

Everolimus might work provided that it crosses the BBB in sufficient amount as to inhibit the mTOR pathways in neurons (and possibly also glia) in key brain areas involved in MSA/PD (e.g., basal ganglia).
Mouse studies and RWE studies are interesting to unveil hypotheses that should be confirmed in placebo-controlled human trials.

So… no one knows whether everolimus is better than rapa or not at crossing the BBB and being neuroprotective…

2 Likes
#171

There is, though it was never published: see this presentation by Steven Spindler at at 10:42.

2 Likes
#172

Never published is not reassuring.

1 Like
#173

Mitochondria only spread cell-to-cell to adjacent cells via tunneling nanotubes, etc. Mitochondriopathies, Parkinson’s, aging muscle, and other diseases involving mitochondrial mutations show focal areas of high mutation burden in afflicted tissues, with other cells and tissues having low mutation burden and unaffected.

#174

Spindler ran a huge ITP-on-steroids operation in the last few years of his research career and a lot of it wound up unpublished when he retired. He was one of the top 5 most competent lifespan study scientists and his methods and powering were robust: if he reported it in any context, it’s credible.

#175

All but one of your studies here involve an acute inflammatory insult such as LPS, which tends to cause BBB leakiness, which might explain why rapa gets in under these circumstances and not under physiological conditions. Also, most involve repair of the brain vasculature itself, which does not require BBB transit.

1 Like
#176

Macrophages move around and distribute mitochondria. EVs move around containing mitochondria.

1 Like
#177

Oh yeah, Spindler is a legendary name in CR and generally longevity field, I’ve been following him for decades. Extremely competent and very credible. His word counts for a lot with me, which is saying something, as I tend to be very resistant to personality driven authority. Spindler studies were always of the highest standards.

1 Like
Parkinson's disease
#178

Are you referencing this paper, or is there another? In addition to being a Chinese group, the control animals were miserably short-lived (median survival 690 days) and survival was only improved 5.9% (to a still-abominable 730.8 days in Empa) in the male mice; that’s pretty much meaningless.

Very good point on the MR, though.

3 Likes