Towards natural mimetics of metformin and rapamycin


Aging is now at the forefront of major challenges faced globally, creating an immediate need for safe, widescale interventions to reduce the burden of chronic disease and extend human healthspan. Metformin and rapamycin are two FDA‐approved mTOR inhibitors proposed for this purpose, exhibiting significant anti‐cancer and anti‐aging properties beyond their current clinical applications. However, each faces issues with approval for off‐label, prophylactic use due to adverse effects. Here, we initiate an effort to identify nutraceuticals—safer, naturally‐occurring compounds—that mimic the antiaging effects of metformin and rapamycin without adverse effects. We applied several bioinformatic approaches and deep learning methods to the Library of Integrated Network‐based Cellular Signatures (LINCS) dataset to map the gene‐ and pathway‐level signatures of metformin and rapamycin and screen for matches among over 800 natural compounds. We then predicted the safety of each compound with an ensemble of deep neural network classifiers. The analysis revealed many novel candidate metformin and rapamycin mimetics, including allantoin and ginsenoside (metformin), epigallocatechin gallate and isoliquiritigenin (rapamycin), and withaferin A (both). Four relatively unexplored compounds also scored well with rapamycin. This work revealed promising candidates for future experimental validation while demonstrating the applications of powerful screening methods for this and similar endeavors.

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I wanted to give something back to this wonderful forum community, as I have been lurking for a while. Plus, I’m sure I’ll learn a lot from comments. I have an interest in applying AI to drug discovery. While this article is from 2017, I liked their approach. One interesting discovery is that Withaferin A from Withania Somnifera (Ashwagandha, winter cherry) may be a mimetic for both rapamycin and metformin, as noted in the abstract.


I saw that a while back, before starting rapamycin, and did take Withaferin A. It’s hard to find, I think due to safety concerns. Many ashwagandha products intentionally keep the Withaferin A content low. I managed to find one product by Life Extension called “Geroprotect Longevity A.I.” with a higher Withaferin A content (along with ginsenosides and GLA), but it’s been discontinued.

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Here’s a Life Extension article about it: Combating Aging via Artificial Intelligence - - Life Extension

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Ashwaghanda is powerful at lowering elevated cortisol (think waking up with your heart pounding) and there is evidence of general anxiety lowering when taken for a few weeks.

I was surprised to see it ranked highly by this algorithm for rapamycin mimetic since it seems so different in effect.

I’ve read theories that it could cause issues with thyroid if taken for a long time. Perhaps something to be careful with.


To say Withaferin A has pleiotropic effects may be an understatement! It would be helpful if we had good Phase I studies to better understand the kinetics and the possible toxicities of this compound. It seems to strongly inhibit the actions of the usual suspects producing inflammation: NF-κB, signaling kinases (e.g., JAK/STAT), heat shock protein 90 (HSP90), Nrf2 and the inflammasome complex. Until the safety of continuous use is better characterized, personally I would only employ it for short periods of time, say a week or less, addressing a particular inflammatory event. There is a Phase I/II oncologic trial ongoing, but it is not a clean study only employing WA.
There is also the issue of interindividual variation in response, and unknown drug-drug interactions.

Interesting, thanks! I wonder why it was discontinued?

I have taken ashwagandha on and off over the years flip-flopping when some new paper either promoted ashwagandha or warned against its use.

I never felt any effect from the amount I was taking so it was never high on my list of supplements. It is often called an adaptogen, which I interpret to mean “we don’t know what it does but it must be good”.

I have never heard of Withaferin A before so I am unfamiliar with the reference. I see some ashwagandha supplements, KSM-66 claiming to be high in withatanolides. Is this another way of saying withaferin A?

“Withanolides are the main active ingredients in ashwagandha”
“Nutricost KSM-66 Ashwagandha Root Extract 600mg, 60 Veggie Caps - High Potency 5% Withanolides - with BioPerine - Full-Spectrum Root Extract”

Would this be enough (5%) to be effective?

Any reason why you don’t want to just use Rapamycin and Metformin?

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Some claims for ashwagandha:

Reduces cortisol levels
Cognitive benefits, promoting enhanced memory and cognitive function.
“Ashwagandha has been found to possess anti-aging properties, potentially supporting longevity”.
Enhances sleep quality.
Ashwagandha can increase testosterone levels.

As I said before; I noticed no subjective benefits from ashwagandha. Maybe I was taking the wrong brand, not enough, or perhaps not noticing the effect on my testosterone levels.

I employ both, and I didn’t mean to imply anything should be substituted in the initial report I cited. We have a lot more safety and efficacy data for rapamycin and metformin than for many of the nutraceuticals noted.


Yes, WA is a withanolide. A pretty good and referenced review of the safety in humans is found here under “clinical data.” One clinical study in men used “ashwagandha root extract 300 mg (5% withanolides).”

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Using ashwagandha/withanolides is not comparable. The Withaferin A component of withanolides is kept as low as possible in most ashwagandha supplements and usually stated as less than a threshold amount, for example “<0.1% Withaferin A.”

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Good point. Amusing that the best studied withanolide, withaferin A is so low in that supplement compared to the less well studied withanolides. Maybe because it is only found in the leaves, as opposed to the other highly structurally similar but less well studied withanolides. Dancing with Ann O’Lide, I can barely keep up!

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Bryan Johnson uses Ashwagandha KSM66. Maybe that’s good enough for me.
After all, he has a team of 30 doctors. :grin:


I did find some ashwagandha that is at least partially derived from leaves.

It is found at Nootropics I have used Nootropics Depot for over a decade and have found them to be a reliable supplier for some hard-to-get supplements.