Safe Rapamycin and Metformin mimetics

Have also been interested in rapamycin and metformin mimetics, if anything to bolster their effects. Believe that creating the same desirable outcomes through multiple pathways (i.e. quieting mTORC1 including reducing senescent effects, and increasing autophagy including NRF2) will avoid rebound/resistance effects and undesirable feedback loops from any particular approach.  Here are a couple of paragraphs pulled out of my WIP supplements & longevity worksheet that considers fisetin as perhaps a (better?) candidate for rapa: 

"For reference, rapamycin binds with FKBP12 forming FKBP12-RAPA complex, which then binds with the FRB domain of mTORC1 (destabilizing it and may interfere with assembly of mTORC2) with a relatively strong affinity of 12 nM (nano-molar, a measure of concentration). Fisetin binds directly with mTOR at a much weaker affinity (~ 11000nM, a much higher concentration required here...almost 1000x more than rapamycin), but at 3 different binding sights. Fisetin also directly inhibits S6K (a.k.a. p70S6K), a downstream effector of mTORC1 ( at ~ 12 times the affinity at 940 nM, or ~ 80x the concentration of rapamycin/mTORC1), whereas, rapamycin doesn't at all. For reference, S6K1 (a phosphorylated version of S6K, by mTORC1) can also participate in a positive feedback loop stimulating more mTORC1 activity (by dampening upstream mTORC1 inhibitors). Taking sufficient fisetin, therefore, could supplement rapamycin (or supplant it altogether?). Rapamycin has roughly 20 times the half-life (~ 62-70 hours) of fisetin (~ 3 hours) and should be taken once every 7-10 days (by the time it's mostly out of the system). To approximate rapamycin efficacy, sufficient fisetin (80x, a feasible 500mg or more, to inhibit downstream S6K, or 1000x, >6,000mg, to directly bind mTORC1, which seems unfeasible) would have to be taken once every 12 hours (twice a day). If just as effective, mTORC1 inhibition via fisetin could avoid potential  inhibition of mTORC2 (gradually/indirectly caused by prolonged high rapamycin exposure) and it's immune signaling functions.

mTORC1 inhibition as chemotherapy (e.g. rapamycin to control some cancers) can invite negative feedback loops from AKT (3-protein complex that serves as an upstream activator of mTORC1), which bypasses mTORC1 suppression by signaling downstream IGF-1 (insulin-like growth factor-1 responsible for growth, especially during the growth spurt during puberty, and for tumor growth). Fisetin, in sufficient doses, indirectly suppresses AKT (via directly binding with upstream PIK3 i.e. PIK3/AKT/mTOR) and directly inhibits MTORC1 (and downstream S6K even more effectively), which explains it's more favorable performance in suppressing cancer growth (besides it's excellent senolytic properties)."

Take a look at the below link. Withaferin A (ashwagandha) is a mimetic of both rapamycin and metformin.

https://www.researchgate.net/publication/287922529_Vitamin_B3_for_depression_Case_report_and_review_of_the_literature

"One of the most significant findings was withaferin A, one of only two only compounds topping the list for similarity to both metformin and rapamycin. Withaferin A was the top-scoring compound for gene-level similarity to metformin using the conventional statistical approach and also displayed significant pathway- and gene-level similarity to rapamycin using both the pathway activation approach and the deep learning approach."

"Withaferin A was one of three compounds we included in the combination explored for metformin similarity. The other two were ginsenoside and GLA [gamma linolenic acid], which also demonstrate anti-aging, anticancer, and anti-disease potential in a number of studies."

I've looked into this extensively and the 3 ingredients mentioned above (as metformin and rapamycin mimetics) can be found in the product called Geroprotect Longevity A.I. from Life Extension. You may want to read this: https://www.lifeextension.com/magazine/2018/4/combat-aging-via-artificial-intelligence