If you’ve been following the latest headlines in the scientific literature about longevity and anti-aging, then you no doubt have heard about metformin. To some scientists, it is a borderline miracle drug, capable of extending lifespan through a host of biological pathways. To others, metformin has some legitimate uses in the treatment of type 2 diabetes, and they remain skeptical about its anti-aging benefits. And still, to a select few, the buzz surrounding metformin in terms of longevity is empty hype. 

If you’re confused about what to think, don’t be. In this article, I am going to share my opinion on metformin and why I am excited about its use in regenerative medicine therapies.

What is Metformin?

Metformin is a widely used drug for the treatment of type 2 diabetes. It is derived from a plant called the French Lilac, which has been used as an herbal remedy for treating excessive urination caused by diabetes since the Middle Ages. Metformin, the drug, was first described in 1922 and approved by the FDA in 1994.

Metformin and Anti-Aging

 Over the last few years, studies have shown that metformin may have life-extending properties, but the drug’s efficacy as an anti-aging remedy is still controversial due to a lack of long-term research. More recently, the controversy is diminishing because some of the bigger names in the field of longevity have been touting it. For instance, Dr. David Sinclair, co-Director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School, takes metformin daily for its anti-aging properties.

As time passes, more anti-aging specialists will likely be using metformin.

Potential Benefits of Metformin

One of the largest areas of interest regarding metformin and anti-aging is how it affects how our bodies process sugars. As you already know, there is overwhelming evidence that consuming large amounts of sugar regularly can speed the process of aging, and conversely, there is little controversy that diets low in sugars may promote longevity.

Some studies have suggested that metformin may work by activating the AMP-activated protein kinase pathway (AMPK), a key master regulator of cellular metabolism. AMPK is a key energy sensor in cells, and it regulates energy balance by sensing changes in the cellular AMP/ATP ratio. When cellular energy levels are low, AMPK kicks in and stimulates energy-producing processes, such as glucose uptake and utilization, and suppresses energy-consuming processes, such as lipid synthesis and protein production.

Metformin has been shown to activate the AMPK pathway by increasing the cellular AMP/ATP ratio. Additionally, AMPK activation by metformin has been shown to improve insulin sensitivity and to have various beneficial effects on cellular metabolism, including reducing oxidative stress and inflammation and promoting cellular survival. These are all essential pillars in the longevity field.

The mTOR Pathway 

Another mechanism that promotes longevity is metformin’s effect on the mTOR pathway. The mTOR (mammalian target of rapamycin) pathway is a central signaling pathway regulating cell growth, proliferation, and metabolism. It is activated by growth factors, hormones, and nutrients and regulates many cellular processes such as protein synthesis, metabolism, and autophagy.

Studies have shown that metformin can inhibit mTOR signaling, leading to decreased cell growth and proliferation and increased autophagy. Autophagy is extremely important when it comes to anti-aging, as it is a cellular process that involves the degradation and recycling of cellular components, including damaged proteins and organelles.

An increase in autophagy is considered beneficial for the cell, as it helps to maintain cellular homeostasis and can have protective effects in various diseases. Studies in animal models have shown that restriction of the mTOR pathway can extend lifespan and delay aging-related diseases.

For example, in mice, reduction of mTOR activity has been shown to increase lifespan and improve healthspan, as well as reduce the incidence of age-related diseases such as cancer, cardiovascular disease, and neurodegeneration. The question is, do these animal studies translate to human beings? This is part of the controversy.

Metformin appears to affect the AMPK and the mTOR pathways in a manner beneficial to longevity. It will also activate the AMPK pathway while at the same time diminishing the response of the mTOR pathway.

Metformin and Gut Bacteria

An important mechanism by which metformin reduces aging is its interaction with gut bacteria. Studies have shown that metformin can alter the composition and diversity of gut bacteria, leading to changes in the production of various metabolites, including short-chain fatty acids, bile acids, and other gut-derived molecules. This can impact glucose metabolism, insulin sensitivity, and other metabolic processes.

Another way metformin interacts with gut bacteria is through its impact on the gut-liver axis. Metformin has been shown to reduce glucose production in the liver and increase insulin sensitivity, which can benefit glucose metabolism. However, it is believed that these effects are mediated, in part, by changes in the gut microbiome, including changes in the populations of specific bacteria that are involved in glucose metabolism and insulin regulation.

In yet a third benefit, metformin has been shown to affect the gut-brain axis, and changes in the gut microbiome may also play a role in these effects. Studies also indicate that metformin can alter gut permeability. Along these lines, metformin appears to affect the production of neurotransmitters and other signaling molecules in the gut, which can influence brain function and behavior.

As we’ve shown, metformin interacts with gut bacteria in several ways, and these interactions are believed to play a crucial role in its effects on glucose metabolism, insulin sensitivity, and other metabolic processes.

Why Metformin is Intriguing 

Metformin is commonly used as a model compound in aging studies because of its potential to extend lifespan and improve healthspan in various model organisms, including yeast, nematodes, fruit flies, and mice. However, metformin is not the only compound being used in anti-aging studies.

Other compounds used in anti-aging studies include rapamycin, a drug initially developed to prevent the rejection of transplanted organs, and pterostilbene, resveratrol, and berberine. These compounds have been shown to extend lifespan and improve healthspan in various model organisms. They are being studied to understand the underlying mechanisms and to determine their potential as anti-aging drugs. Other compounds being studied in anti-aging research include sirtuin activators, NAD+ precursors, growth hormone receptor antagonists, and drugs targeting specific aging pathways, such as the insulin/IGF-1 signaling pathway.

Exercise and Metformin 

One ongoing controversy in the anti-aging world is whether exercise and metformin complement each other or cancel each other out. To answer this, we know that exercise and metformin improve fitness, blood sugar levels, and insulin sensitivity. They both boost mitochondrial function, work the same pathways, and have similar effects.

The question then arises: Will taking metformin with your exercise regimen amplify the results? We don’t know for sure, but a recent study shows that may not be the case. In fact, according to this one study, exercise, and metformin may cancel each other out.

In the study, the group of participants taking metformin while exercising had about half the gains in the fitness of those taking a placebo with their training. They had negligible improvement in insulin sensitivity.

Finally, the people on the placebo had about a 25% rise in mitochondria respiration, while those on metformin saw slight if any, improvement. But you have to keep in mind that this is a small study, and it may have flaws that negate the results. It’s simply too early to tell.

According to most of the research I have uncovered, it is recommended that people who combine metformin and exercise continue that regimen unless more specific evidence is found.

For instance, Dr. David Sinclair feels metformin probably works as a hormetic substance, meaning that it causes minor damage to our cells, putting them in a repair and protection state. This damage inhibits mitochondrial function so that the mitochondria will repair and protect themselves better. However, exercise also “damages” the mitochondria somewhat. This damage will result in the repair of the mitochondria, which is one of the health benefits of exercise. Thus, some stress on the cells is beneficial, but too much may result in damage that is not easily repaired.  Dr. Sinclair does not take metformin when he exercises. Might there be a better alternative?

Alternatives to Metformin 

One drug that I am particularly fond of is berberine, which I switched to from metformin many years ago. Berberine is a chemical compound that is similar to metformin in some ways but different in other critical areas.

Metformin works primarily by reducing glucose production in the liver and increasing insulin sensitivity in peripheral tissues. It is believed to activate AMP-activated protein kinase (AMPK), a key regulator of metabolism, which increases insulin sensitivity and improved glucose control.

Both metformin and berberine are known to stimulate the AMP-activated protein kinase (AMPK) pathway. However, berberine is thought to be a more potent activator of the AMPK pathway than metformin. Berberine works by several mechanisms, including activation of AMPK, inhibiting glucose absorption in the gut, and improving insulin sensitivity in peripheral tissues.

Berberine has also been shown to have antibacterial and anti-inflammatory properties, which may contribute to its glucose-lowering effects. Berberine also influences the gut microbiome, the community of microorganisms that reside in the digestive tract. Some studies even suggest that it can increase the abundance of certain beneficial bacteria and decrease the number of harmful bacteria.

As an added benefit, no studies show that berberine has the same potential exercise-canceling benefits as metformin. Thus, I hedge my bets and, at least for now, take berberine over metformin for anti-aging.

The evidence is strong in the field of anti-aging that metformin and berberine have solid anti-aging attributes as well as potential anti-cancer properties based on laboratory and epidemiological studies.

Lastly, realize that several modalities used in our clinic can offer similar stimulation of anti-aging pathways.

These include EBO2Red Light TherapyInfrared SaunaHyperbaric Oxygen Therapy, and a few others.

And this related piece will provide valuable information on another modality: 7 Anti-Aging, Disease Fighting Benefits of Therapeutic Intermittent Hypoxic Training.

The real benefits occur when one combines metformin or berberine with these exciting modalities!

In addition, if you’ve been exercising and you’d like to level up your focus, you will enjoy Carissa Raver’s article here: 3 Breathing Exercises to Calm Your Nerves and Improve Performance

– Dr. P


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