Rapamycin vs Metformin

I've got a supportive MD who runs an aging clinic I'm seeing soon and am considering next steps. So far I've ...

  • Fixed all the basics (hormones, glucose, BP, ...)
  • Taking 2000 metformin daily
  • Did the NAD patches, plus daily booster

 

Canonically the next step would be Rapamycin, however I've heard rumors that if you're good with Metformin activating AMPK that perhaps Rapamycin isn't necessary. If it's still 'a good idea' or at least not a bad idea, thoughts? 

From the March Life Extension magazine page 98

Human Strategies to Suppress Excess mTOR

Rapamycin is being studied in humans to assess its ability to suppress excess mTOR and potentially reverse age-related pathologies. 

The most efficient way for people to suppress mTOR today is to activate cellular AMPK.

This can be done with the drug metformin, intermittent fasting/calorie restriction, and/or AMPK activating nutrients like gynostemma and hesperidia

The interesting thing is that the article is about the Canine Rapamycin project to suppress mTOR, yet at the end seems to be saying that Metformin is the best way to go about it via AMPK 

Further in this article from Feb 2018 by Bill, the sequence is

  1. Living causes cellular waste, which is removed via autophagy
  2. "Recent discoveries show that almost every intervention proven to extend healthy lifespan involves activation of autophagy (removing toxic cellular waste)"
  3. "One of the safest and most effective methods to optimize autophagy is by activating an enzyme in our cells called AMPK"
  4. "AMPK performs its fat-removing process, in part, by regulating a protein called mTOR"
  5. The most studied mechanism of metformin action is its ability to boost AMPK activity.

 

So it would seem you can use Metformin to activate AMPK and thereby regulate mTOR. Or you can go after mTOR directly with Rapamycin. Given the track record of Metformin that would seem the better route, and if you're already taking it then, in the absence of other information, adding Rapamycin would seem to be overdoing it. 

Addition: OK I found a reference

BF: Most people eat too much and this causes mTOR to be chronically elevated, which may preclude optimal results using the other interventions. Rapamycin directly suppresses mTOR. So we believe that inducing autophagy (removal of accumulated cellular waste), which happens when mTOR is suppressed, is a logical first step. What we are finding, however, is that most of our supporters already take metformin, practice intermittent fasting, and/or ingest nutrients that boost a cellular enzyme called AMPK, which indirectly suppresses mTOR. So we feel they may be able to skip rapamycin at first and proceed to boosting their NAD+ as I next describe. We will know more about the additive benefits of rapamycin when a clinical trial we are helping fund wraps up in a few months.

There you go, if you are taking Metformin, practice fasting, supplements and diet, then the expense and trouble of Rapamycin is probably not necessary. 

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  • I'm actually wondering if the blocking of gluconeogenesis may be a downside to using Metformin in combination with prolonged fasting. I would be curious to learn if combining it with Rapamycin would give the body flexibility to rely on gluconeogenesis when it is needed.

    This is interesting:

    Anti-aging combinations

    Rapamycin (or another rapalog) should be a cornerstone of anti-aging combinations (Figure (Figure1),1), given its universal anti-aging effect and the ability to delay almost all diseases of aging.

    Rapamycin and metformin: Both drugs extend lifespan in animals and have non- overlapping effects. In addition, they may, in theory, cancel possible metabolic side-effects of each other. As we discussed here (see rapamycin section) as well as in [31, 130], rapamycin in different settings may either increase or decrease insulin sensitivity. Similarly, calorie restriction increases insulin sensitivity, whereas severe calorie restriction (starvation) decreases it [129, 245]. In any case, rapamycin prolongs life span, indicating that insulin resistance is benevolent [130]. Unfortunately, the fear of this benevolent ‘side effect’ is delaying applications of rapamycin for prevention of age-related diseases. The simplest approach is to monitor glucose levels in individuals taking rapamycin. In addition, metformin, an anti-diabetic drug that reverses insulin resistance, could be combined with rapamycin.

    And vice verse, metformin may potentially increase blood lactate levels. Rapamycin decreases lactate production [164]. Each drug prolongs lifespan in mice, prevents cancer, atherosclerosis, and other diseases of aging.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482593/

    I have a prescription for Metformin but can maintain a FBG in the low 80's without it. I want to build up the ability to fast to 72 hours. My understanding is that the body relies on gluconeogenesis to maintain glucose when fasting over multiple days. I could really use more information.

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