Safe Rapamycin and Metformin mimetics

EGCG and Ginseng are safe mimetics to rapamycin and metformin respectively based off one of Insilico Medicine's AI. I only have a bachelor's degree in biomedicine, but I have studied this research for a while and I think combining these would be one of the best gerosupp approaches out there. Lots of studies indicating rapamycin and metformin acting synergistic together. I started taking for a while now and I can feel the health effects. It even acts as a nootropic

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  • 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)."

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    • UB great research. I have some liposomal Fisetin and have been researching methionine and cysteine restriction as another way to 8nduce autophagy

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      • Juan Daw
      • saxxnviolins
      • 7 mths ago
      • Reported - view

      UB Nrf2 increase can be achieved by intake of sulforaphane, found in cruciferous vegetables. There are many vidoes on this by Rhonda Patrick, interviewing Dr. Jed Fahey. Best source is broccoli seeds.

       

      Nrf2 can also be increased by oleanolic acid, found in olive oil. 

       

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215260/

       

      Various classes of phytochemicals have been shown to activate Nrf2 pathway and reduce APAP toxicity (Table 1). Sauchinone, a polyphenol, reduces the impact of APAP overdose by enhancing Nrf2 phosphorylation via protein kinase C-δ (PKCδ) and decreasing interaction amongst Nrf2 and Keap1 [34]. Salvianolic acid B reduces APAP-induced liver injury via phosphoinositide-3-kinase- (PI3K-) and PKC-mediated Nrf2 activation, resulting in enhanced HO-1 and GCLC expressions [35]. Sulforaphane (an isothiocyanate found in cruciferous vegetables, namely, cauliflower, broccoli, kale, cole crops, cabbage, collards, brussels sprouts, and mustard) and oleanolic acid (a triterpenoid found in olives) both reduce APAP-induced oxidative stress and liver injury via Nrf2 and related antioxidant gene activation [3637]. A recent study from our laboratory evaluated the hepatoprotective potential of withaferin A, an active ingredient of Withania somnifera. We observed that withaferin A treatment 1 h after APAP intoxication activates Nrf2 responsive genes such as NQO1 and GCLC to reduce oxidative stress and subsequent liver injury [38]. An in vitro study, using rat hepatocytes, reported that ginsenoside Rg3 (a ginseng saponin) upregulates antioxidant genes (GCLC, GCLM) and basolateral MRPs via Nrf2 activation [39].

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      • UB
      • U_Bednarzik
      • 7 mths ago
      • Reported - view

      Juan Daw Thanks for the link and info. If you could only take one supplement to directly increase NRF2/glutathione levels than Sulforaphane  would be overwhelmingly the best choice at over 80% oral bio-availability. Have watched many Rhonda Patrick videos explaining dosages and how to get the most out of it. Both flavanoids, fisetin and GSPE (grape-seed extract), can prolong NRF2 life/effectiveness by interfering with ubiquitination proteins (that would normally degrade it in about 15 minutes). In a similar way, another flavanoid, apigenin, inhibits CD38 from degrading NAD+ too quickly also.

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  • 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."

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      • UB
      • U_Bednarzik
      • 7 mths ago
      • Reported - view

      Juan Daw  Thanks for the suggestion. Haven't found any direct studies yet regarding Withaferin A mechanism of action relating to MTORC1 inhibition, but do see several autophagy related studies that could directly lead to MTORC1 suppression. Sounds like a very promising (natural) compound...can't wait for more research on it.

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  • 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

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      • UB
      • U_Bednarzik
      • 7 mths ago
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      cjacek  Thanks for the link, just read through it. Like to get more into the underlying mechanisms of supplements/methods so further researched Ashwagandha (incl. Withaferin A) and found that it mimicked Rapamycin's inhibition of mTORC1 by binding with HSP90 (Heat Shock Protein 90), which acts as a protective chaperone protein for PIK3 (e.g. PIK3/AKT/mTORC1 pathway). Tying up HSP90 opens up PIK3 to degradation from ubiquitination proteins (always running around to make sure signaling proteins don't last forever in your system), which then deprives further signaling/activation of mTORC1. Believe that Withaferin A may help supplement Fisetin when trying to mimic (if not out-perform) Rapamycin if taken at the correct dosages. Perhaps taking all three at reduced doses could make even a more effective mTORC1 inhibitor?

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