Considering the low/accessible switching cost vs rapamycin, and the apparent superior pharmacology/translation, warrants serious consideration as optional mTOR manipulator towards our ultimate objective.
For me, the biggest insight in this brief exchange is that INTERMITTENT Rapamycin does not continuously depress mTOR vs daily (see below). Since the rapamycin/mice studies showed continuous mTOR reduction, I believe for human translation, we need to at least give ourselves a superior shot at efficacy by trying to more consistently inhibiting mTOR during our dosing protocols. And side effects is a huge human impediment, so this is added translation bonus with Everolimus.
Can we better harness Everolimus with perhaps more frequent, lesser dosage, sufficient AUC for more consistent mTOR inhibition, without the side effects?
@rapadamin Possible rebrand, “everolimus.news”? Did you already register the name? 
Perhaps already covered elsewhere, but brief refresh:
Mechanism
Compared with the parent compound rapamycin everolimus is more water-soluble. Compared to rapamycin, everolimus is more selective for the mTORC1 protein complex, with little impact on the mTORC2 complex. This can lead to a hyper-activation of the kinase AKT via inhibition on the mTORC1 negative feedback loop, while not inhibiting the mTORC2 positive feedback to AKT. This AKT elevation can lead to longer survival in some cell types. Thus, everolimus has important effects on cell growth, cell proliferation and cell survival.
mTORC1 inhibition by everolimus has been shown to normalize tumor blood vessels, to increase tumor-infiltrating lymphocytes, and to improve adoptive cell transfer therapy.
Additionally, mTORC2 is believed to play an important role in glucose metabolism and the immune system, suggesting that selective inhibition of mTORC1 by drugs such as everolimus could achieve many of the benefits of rapamycin without the associated glucose intolerance.
Use in aging
Inhibition of mTOR, the molecular target of everolimus, extends the lifespan of model organisms including mice, and mTOR inhibition has been suggested as an anti-aging therapy. Everolimus was used in a clinical trial by Novartis, and short-term treatment was shown to enhance the response to the influenza vaccine in the elderly, possible by reversing immunosenescence. Everolimus treatment of mice results in reduced metabolic side effects compared to sirolimus (below reference).
Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system (Lamming 2016)
“We find that the FDA approved rapamycin analogs everolimus and temsirolimus
efficiently inhibit mTORC1 while having a reduced impact on glucose and pyruvate tolerance. Our results suggest that many of the negative side effects of rapamycin treatment can be mitigated through intermittent dosing or the use of rapamycin analogs”
But here’s the kicker for me…
“As we anticipated following our preliminary experiments, our intermittent rapamycin regimen does not continuously inhibit mTORC1 throughout the 5-day period in mouse tissues (Fig. 3).”
I don’t recall a mouse longevity study with rapamycin, which produced significant lifespan extension, that was intermittent dosing, during it’s treatment window. Mice have a very high metabolism, so they need constant dosing to sustain blood rapamycin levels…but regardless in terms of human translation, the key point is that the mice were exposed to CONTINUOUS mTOR inhibition, not intermittent.
