Science 101

How Metformin, A Diabetes Drug, Got Into the Aging Market

Promising early results have anti-aging scientists eyeing one of the most-prescribed drugs on the planet.

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The winding story of the so-called miracle drug metformin begins with a flower. Galega Officinalis, or French lilac, is a flowering herb common to the European countryside that has been used for three centuries to treat fever, plague, and frequent urination (the latter of which is a sign of diabetes). By 1918, the active compound in French lilac, guanidine, was found to lower blood sugar significantly, and starting in the 1920s derivatives of guanidine were used to treat diabetes — often with tremors, vomiting and diarrhea, due to high toxicity. 

It wasn’t until the 1950s that a physician and pharmacologist named Jean Sterne isolated the drug we now know as metformin. Sterne originally called it “glucophage,” which roughly translated means glucose eater in Greek. It was much safer and more effective than the previous versions of guanidine, but the earlier experience made scientists very weary. But finally, after years of cautious study, metformin was approved for use in the United States by the FDA in 1995. Today, the drug is the most commonly prescribed drug for type 2 diabetes, which affects more than 400 million people globally.

Scientists have also noted that metformin’s benefits extend well beyond diabetes. Numerous mouse studies have shown that even low doses of the drug can increase lifespan and keep rodents healthier for longer in part by preventing cancer. Human studies have found that people who take it have a lower risk for cardiovascular disease and actually live 15% longer than diabetics on other regimens as well as people without diabetes. 

This bevy of promising results has led to a hope that metformin could become the first drug to treat aging itself. But as we continue to learn more about metformin, there are growing signs that might just be too good to be true. 

How Does Metformin Work?

Just as a dam helps manage the flow of a body of water, metformin works in a similar way to lower the amount of glucose released by the liver into the bloodstream, thus maintaining lower blood sugar levels. In people with diabetes, insulin stops working to transfer glucose (blood sugar) to storage, so glucose levels rise sharply.

That’s the big picture of metformin’s effects, and the reasoning behind its current use. But how exactly metformin is doing this is complex and not fully understood. The most likely main mechanism by which metformin works is by upregulating a pathway called AMP-activated kinase (AMPK), which is relevant to cell metabolism and nutrient signalling. But we know now that metformin also acts on a number of other cellular pathways, such that it also facilitates DNA repair, decreases oxidative stress, and lowers chronic inflammation. It could be that metformin has multiple effects on several different targets, or it could be that by working on one pathway (AMPK, perhaps) it kickstarts a chain reaction that leads to all of the other observed consequences.

What Does Aging Have To Do With It?

Although the U.S. FDA doesn’t consider aging a disease itself (not yet, anyway, though the World Health Organization has a different take), aging is the most important risk factor for a range of serious diseases — heart disease, stroke, diabetes, cancer, even neurodegenerative diseases like Alzheimer’s. Over the past few decades remarkable progress has been made in understanding the biology of aging itself, so that perhaps one day we can delay aging, and prevent many instances of these related diseases so that even if people don’t live longer, they can live better for longer. Scientists call this “increasing healthspan.” We know now that on the cellular level, aging involves a cascade of changes that reinforce one another and lead to disease and breakdown of your normal processes. These include things like deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, and more.

Metformin appears to target a number of these aging-related mechanisms. For example, we know that AMPK signalling function declines with age, which then impairs cellular metabolism and leads to a number of the cellular changes that scientists now recognize as the hallmarks of aging. If metformin works by upregulating AMPK, then it’s possible that metformin can prevent this breakdown and thus delay the aging process itself, as well as the multitude of diseases related to it.

A veritable avalanche of research already supports this hypothesis. In fact, when taken all together, it seems that there isn’t much this superdrug can’t do. One study found that diabetic patients who were taking metformin had a 46 percent lower risk of developing head and neck cancers compared to non-diabetic patients. Research has found similar positive effects of metformin on the risk of stomach cancer. Another study of more than 24,000 patients found that in people with early-stage colon and rectum cancers, metformin use improved overall rates survival by 31 percent, and cancer-specific survival by 42 percent.

Metformin may also help prevent heart disease. Research found that taking metformin can help prevent the development of atherosclerosis, a hardening of the arteries that’s a hallmark of cardiovascular disease. It can even play a role in weight loss. Because of metformin’s effects on activating AMPK, studies suggest that it may help people lower their body weight and reduce their systolic blood pressure.  

Finally, metformin may also have neuroprotective benefits to help improve brain health. A 2016 study showed that taking metformin improved memory recall in a group of older adults with mild cognitive impairment (a precursor symptom to Alzheimer’s and other dementias).

So Why Aren’t We Using Metformin Yet For Aging?

So far all of the research done on metformin looks at various specific endpoints, whether it’s the cessation of diabetes symptoms or the prevention of atherosclerosis. Many of the studies, especially those focusing on cancer, are only observational, meaning these results are subject to confounding factors. As promising as the current results are so far, in order to support widespread use for metformin as a true anti-aging drug, we need to do large-scale placebo-controlled trials of the drug in older people to see if it works to extend healthspan. If metformin really is fundamentally working on aging as many scientists believe, we should see reductions in all of the age-related diseases all together. 

Currently, a team of scientists is working on getting funding for a study that does just that. The TAME (Targeting Aging with Metformin) Trial entails a series of nationwide, six-year clinical trials of more than 3,000 people between the ages of 65-79. These trials will test whether metformin can delay the onset of typical age-related diseases, such as cardiovascular disease, cancer, and cognitive decline, compared against placebo. Positive results from this trial could change medicine as we know it because it would prove the possibility of targeting aging itself— something that has never been done before. This could lead to not only to the approved use of metformin, but industry interest in further funding aging research and developing even better drugs to treat it. 

But for now, this is still just hopeful — at least for now. TAME devotees are having trouble getting their big idea funded. In light of that, some doctors are jumping the gun by prescribing metformin off-label as an anti-aging drug. Although we can reasonably assume based on the millions who take it with minimal side effects that its a relatively safe drug (and certainly the small risk of side effects are outweighed by the huge risks of having diabetes), there are still way too many questions to recommend experimentation. For example, a small 2019 study found that metformin supplementation in non-diabetic older people diminished the health benefits of exercise. Meanwhile, another small clinical study testing a cocktail of drugs, which included metformin, growth hormone, and another diabetic drug (dehydroepiandrosterone, or DHEA) found rejuvenated immune systems and genomic differences in participants’ biological ages. All of this together suggests that metformin’s use in healthy people really could be an entirely different can of worms.

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