Life Extension Magazine®
Doctor aided by AI in finding overlapping metformin compounds

Artificial Intelligence Identifies Longevity Pathways

Using deep learning artificial intelligence, scientists identified plant compounds that modulate many of the same pro-longevity pathways as metformin.

Scientifically reviewed by: Dr. Gary Gonzalez, MD, on October 2020. Written By Celia Stanton.

The drug metformin, prescribed to control blood sugar, has been shown to modulate many anti-aging pathways.1-5

In one animal study, metformin treatment led to a 14% extension of lifespan when treatment was begun early in life. Another rodent study with long-term metformin treatment also extended life.6,7

These data applied to humans would equate to prolonging an average human life from roughly 79 years to 90 years.

A metformin study in the C. elegans model of aging led to a remarkable 33% lifespan extension.8

A 2014 human study found that type II diabetics treated with metformin live longer than non-diabetics (who did not take metformin).9

Diabetics usually die sooner than non-diabetics, making this study showing diabetics taking metformin live longer than non-diabetics remarkable.

Seeking a metformin alternative, scientists used artificial intelligence (A.I.) technology to conduct a vast search for plant-based nutrients that mimic metformin’s effects.

They were able to identify three compounds that modulate many of the same pro-longevity pathways as metformin:1

  • Withaferin A
  • Ginsenoside Rg3
  • Gamma-linolenic acid

These three compounds, when highly concentrated, function in overlapping and distinct ways to promote expression of longevity pathways.

Metformin Extends Lifespan

Prescription for metformin

Metformin was first inspired by a nutrient found in a flowering plant known as French lilac.3

It lowers glucose levels via several mechanisms.

Much of metformin’s ability to improve insulin sensitivity is due to increasing a cellular enzyme called AMPK, considered a master regulator of cell metabolism.3

Increasing AMPK activity is an important target for anti-aging interventions.2

This ability of metformin to prevent age-related disease has been observed in humans.10-13

Based on its ability to extend life, a large, multi-site ($70 million) human trial is underway to ascertain if metformin can treat aging itself, just like chronic disease.14

How Metformin Fights Aging

Inspired by metformin’s remarkable longevity benefits, scientists set out to find alternatives in botanical compounds.1

Their first step was to identify precisely how metformin extends life. Several studies of metformin have shown that it affects cellular pathways tied to aging, including:2,4,15-21

  • Stimulating AMPK, which helps balance mTOR and improves cellular metabolism and energy production,
  • Decreasing levels of IGF-1, a hormone that has been found to be lowest in people who live exceptionally long lives, and
  • Activating SIRT1, which regulates cellular health and is considered a longevity enzyme.

Through these effects and others, metformin can protect cells and tissues from the ravages of time that would otherwise lead to degeneration, dysfunction, and disease.

As a result of all these actions, metformin:2

  • Improves metabolic health, maintaining insulin sensitivity, improving glucose control, and reducing production of potentially toxic byproducts of metabolism,
  • Protects cellular structures from damage and degradation, including maintaining healthy proteins and DNA,
  • Promotes cellular “housekeeping” (known as autophagy), which rids the body of old, damaged structures and rejuvenates it with healthy replacements, and
  • Reduces harmful chronic inflammation and cellular senescence, which rob tissues of their function.

Using A.I. to Find Alternatives

Scientist teaching AI to find compound overlaps

The next step was to compare metformin’s actions with those of hundreds of plant-based compounds and see where the effects overlap.

In all, scientists identified 871 compounds that mimic metformin’s actions.

Sifting through this vast network of nutrients and their widespread interconnections would be practically impossible if it weren’t for the speed of artificial intelligence to explore these data.

Using deep-learning A.I., researchers found nutrients that regulate the same longevity pathways that metformin does. The artificial intelligence network was able to learn from these data and identify specific nutrients that most closely mimic the effects of metformin.1

A Three-Nutrient Combination

The results of the A.I. study revealed three nutrients that, taken together, would affect most of the same longevity pathways as metformin.

Some of the effects of these compounds overlap, bolstering the anti-aging impact compared to any one alone.

However, each one of the three compounds also confers unique and distinct benefits that sets it apart from the others.

Withaferin A

Withaferin A is an ingredient derived from ashwagandha, a plant that has been used for centuries in traditional Indian medicine to relieve stress, increase energy, and boost concentration.

Like metformin, withaferin A increases AMPK signaling and inhibits mTOR.22,23

What you need to know

Compounds Mimic Metformin’s Life-Extending Properties

  • Metformin is a prescription drug used to treat patients with type II diabetes.
  • In addition to aiding in the control of blood sugar, metformin has been found to have several anti-aging properties, extending lifespan and healthspan in animal models and humans.
  • Inspired by metformin, scientists used advanced artificial intelligence technology to investigate and identify plant-based nutrients that mimic the properties of the drug.
  • The scientists found three compounds that have both overlapping and distinct properties closely resembling those of metformin: withaferin A, ginsenoside Rg3, and gamma-linolenic acid.
  • A combination of all three nutrients acts on similar health- and longevity-promoting pathways as metformin.

As a result, withaferin A has been shown to have beneficial effects on metabolism. In animal models, it blocked formation of new fat tissue, leading to weight loss, and improved insulin sensitivity and glucose control.24,25

Preclinical and animal models have demonstrated that withaferin A can also help maintain healthy protein synthesis inside cells, helping to shield them from some types of degeneration that occur with advancing age and disease.26-29

Ginsenoside Rg3

The ginsenosides are a group of compounds isolated from Panax ginseng (Asian ginseng), another plant widely used in traditional herbal medicine for a very wide range of indications.

Ginsenoside Rg3 activates AMPK, like metformin does.30-33 In addition, in cell and animal models it has shown potent activity to help promote the resolution of chronic inflammation.34,35

Practically all age-related diseases, from cardio-vascular disease to cancer, have inflammation as a major contributing factor. Resolving chronic inflammation is one of the most promising potential ways to lower risk of disease and extend lifespan.

Like withaferin A, but through different mechanisms, ginsenoside Rg3 also prevented the degeneration of critical cellular structures like the mitochondria and cellular membranes in rodent models.36,37

Even more impressive, it has been shown to activate SIRT1 in a rat study.38 The sirtuins, and SIRT1 in particular, are signaling proteins that shield cells from age-related damage and dysfunction. Activation of SIRT1 has been shown in countless models to extend lifespan.39

Gamma-Linolenic Acid

Borage seeds, ashwagandha, and ginseng

A fatty acid found in various plants, gamma-linolenic acid (GLA) can be isolated from borage seed oil, among other sources.

Gamma-linolenic acid has been shown in clinical trials to effectively treat inflammatory conditions.40-42

In one, it significantly improved quality of life in patients with rheumatoid arthritis, reducing the swelling, stiffness, and pain in joints that is caused by chronic autoimmune inflammation.42


Doctor examining artificial intelligence findings

Metformin is a prescription medication which has been shown in animals and humans to improve long-evity via several well-established mechanisms.

Scientists have used deep-learning artificial intelligence technology to scour the natural world for nutrients that have similar life-extending properties as metformin.

This extensive search revealed three ingredients with combined effects closely resembling those of metformin: withaferin A, ginsenoside Rg3, and gamma-linolenic acid.

These three compounds, when provided in sufficient potencies, work in overlapping and distinct ways to promote the expression of life- and health-extending pathways in much the same way as metformin.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.


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