Had a look through this paper.
Potential therapeutic effects of mTOR inhibition in atherosclerosis (2015)
Many good references, in vitro, in vivo, and clinical translation.
With respect to the mTOR positive indications from lab models, this table reproduced herein. Looking at the “serum lipids” column, you see most all of the models, lipids and TG are unchanged? Yet, our current concern is clinical translation where we know in humans, higher dosing WILL elevate TG/lipids? So how does that change animal model translation?
“Unfortunately, rapalogs are known to trigger diverse undesirable effects owing to mTORC1 resistance or mTORC2 inhibition. These adverse effects include dyslipidaemia and insulin resistance, both known triggers of atherosclerosis. Several strategies, such as combination therapy with statins and metformin, have been suggested to oppose rapalog-mediated adverse effects” (combination therapy, more variables, interactions, risks)
Everolimus was apparently superior to Rapamycin, but most everyone here is on Rapamycin?
Side commentary on cancer in this paper, drilled down.
“When it was given chronically, however, rapamycin paradoxically led to glucose intolerance in mice, rats and humans. This effect was, at least partly, mediated by mTORC2 inhibition following chronic rapalog administration as mTORC2 has recently been identified to be a critical mediator for insulin sensitivity: another explanation is mTORC1 resistance following chronic rapalog treatment. In vitro experiments using renal carcinoma cells (RCC) revealed that long-term everolimus treatment results in hyperphosphorylation of S6rp, a crucial mediator in insulin resistance. ***Along this line, we have obtained in vivo evidence that chronic inhibition of mTORC1 in mice treated with everolimus paradoxically results in over-activation of mTORC1 as well as in diminished autophagy (Kurdi et al., unpublished results). The ability of rapalogs to shift their actions based on the duration of their administration or dosage is still poorly investigated, despite its importance in the clinic. In antitumour therapy, for example, chronic administration of rapalogs is known to induce resistance to the drugs through different mechanisms. So still many questions in human usage.”
I looked for the published results
Continuous administration of the mTORC1 inhibitor everolimus induces tolerance and decreases autophagy in mice
Everolimus at 1.5 mg·kg per day, various time models (about 9 mg/day for 70kg human)
KEY RESULTS
As expected, everolimus inhibited mTORC1 and stimulated autophagy in the liver after 3 days of treatment. However, continuous administration for 28 days resulted in hyperactivation of the Akt1-mTORC1 pathway accompanied by a remarkable decrease in autophagy markers. Everolimus given intermittently for 56 days partially rescued mTORC1 sensitivity to the drug but without inducing autophagy. The failure to induce autophagy following long-term everolimus administration was due to uncoupling of the mTORC1 substrate unc-51 like autophagy activating kinase 1." Yikes
CONCLUSIONS AND IMPLICATIONS
Our data encourage the use of intermittent everolimus regimens to prevent tolerance and to extend its activity
(my sense of the literature on cancer/transplant studies with Rapamycin, where results were not that great (another drill), patients would be considered to be on “chronic” administration, min trough/AUC level? But the seminal cancer/GFJ study measured mTOR inhibition early on, but did they follow these patients over a long period of time and re-measure mTOR??)
“A plausible alternative explanation (mTOR1 resistance) might relate to the resistance to everolimus following long-term treatment, which is a clinically relevant and well-described phenomenon in renal cell carcinoma (RCC), prostate cancer and some other tumour types. These tumours, while initially reacting well to everolimus therapy, often progress to a resistant form in the long run. It is therefore tempting to speculate that analogous to a tumour exposed to long-term mTORC1 inhibition, the high synthesis rate of liver cells drives the initiation of adaptation mechanisms, resulting in hyperactivation of the Akt1-mTORC1 pathway and drug tolerance”
Of course, they are high dose, chronic administration models. But how to reconcile this finding with CHRONIC “Rapamycin” mice studies (mTOR is inhibited), where cancer is delayed, and longevity increased? In humans, clearly chronic administration leads to resistance? It’s a matter of dosing and the “right” mTOR inhibition level…balancing cancer and CAD risks??
Without TOR assays, flying blind…
