Meet Metformin – and It’s Anti-Aging Superpowers

By now, my readers may be aware of my interest in longevity-focused medicine, particularly in light of all of the exciting anti-aging and longevity research and promising treatments making news almost every day.

To be sure, a healthy diet, physical activity and stress management are still, and for the foreseeable future, the best insurance we can get to support a long, vigorous life. But researchers are continuing to chip away at the biological mechanisms that explain how and why we age, and account for the physiological changes that make us “old,” and ultimately lead to our demise. If we now know a good bit about this biology – I’ve written about a number of these topics — a question naturally comes up. Aren’t we at a point where we can develop treatments that attack aging head-on? And the answer is (sorry, if this doesn’t completely satisfy), we seem to be getting very close by the day. In fact, we may have already done so on a few fronts, but only now are we starting to put the pieces together.

One treatment that’s somewhat unintentionally made the biggest longevity splash is the widely-prescribed medication metformin, which was first discovered, in its natural form, in the 1920s, first synthesized and prescribed (in France) in the late ‘50s, and readily available in the U.S. since 1995. Though for decades, its primary job has been to help millions of people manage their type 2 diabetes, in addition, metformin may be the key to slowing the aging process for millions more. Here’s what you need to know:

A longer, healthier life may be metformin’s superpower.

Metformin is the most commonly prescribed drug to treat type 2 diabetes. It’s generic and hence relatively cheap, and it’s remarkably good at making the body more sensitive to insulin — it helps diabetics clear glucose from the bloodstream with the less-than-normal amounts of insulin their bodies produce. None of this should be news. But bolder claims for the therapeutic power of metformin have been advanced, especially by one influential researcher, Dr. Nir Barzelai at the Albert Einstein College of Medicine. He took his inspiration from studies that showed that older type 2 diabetics taking metformin lived longer than a comparison group, not diabetic, not taking metformin. Further positive results from animal research bolstered his theory that the therapeutic effect of the drug went beyond blood sugar control, beyond even the reduction in cardiovascular disease that you might expect. (Diabetics have a much higher risk of heart attack and stroke.) He surmised that the drug was altering some basic mechanisms of aging, molecules like mTOR and AMK, that regulate, at a deep level, how the body operates.

Reprogramming the human machine.

When we’re young, our bodies are programmed to get bigger and stronger and to reach sexual maturity. After our prime reproductive years, evolution doesn’t care what happens to us (we’ve already passed our genes down to the next generation, or had the chance to), and that same pro-growth strategy slowly poisons us. We get less good at taking out the trash that builds up inside the cells (autophagy); energy-burning generates more waste (“free radicals”); cells get damaged and hang around, gumming up the works; inflammation keeps increasing. Barzelai, and others, suspect that metformin is dialing down growth and dialing up cell maintenance, which would account for the metformin group seeming to suffer from less disease across the board and, on average, living longer. In other words, it might be helping the drug-takers become more like the centenarians he had famously studied. Not only did the centenarians live much longer than average, but more significantly, they stayed healthy for decades longer, until they hit some internal age limit and then died relatively quickly, i.e., the end that most of us would choose. Could metformin be the ticket, or a ticket, for the rest of us who weren’t born with those fortunate genes?

Shouldn’t we know the answer by now?

The answer is yes. Barzilai has had a research trial ready to go for some years now, a study that will look at two groups of 1,500 older subjects, one on metformin, one not, nobody diabetic, to see if the drug group, on average, develops the common “diseases of aging” (heart disease, dementia, cancer) more slowly than the non-drug group over the course of six years. The NIH has given its tentative blessing but, frustratingly, the funding is still not in place. As virtually everyone in the anti-aging field has pointed out, the medical establishment is so locked into the traditional mindset of researching diseases one by one that the idea of treating the aging process, the thing that underlies all the severe chronic diseases, gives them the willies. Even in the case of metformin which has successfully been prescribed for one condition, diabetes, for over sixty years and has an excellent safety record.

Cause for optimism.

Admittedly, some of the older studies that suggested that metformin slowed down disease, for diabetics and non-diabetics alike, had design flaws and we simply don’t know how or if the positive results from the animal research will translate to humans. Still, the research landscape is, at the least, promising. One meta-analysis of over fifty studies found that diabetics on metformin had fewer deaths, from any disease, than non-diabetics not taking the drug. In one pilot study of a group of people with mild cognitive impairment, taking metformin for only eight weeks was associated with better cognitive performance. Another study found a 51% decrease in the risk of cognitive impairment, with the biggest benefit seen in patients who’d been on the drug for more than six years. The metformin-cancer connection is far from pinned down but one large meta-analysis (a study of the existing studies) found that people with diabetes on metformin suffered 34% fewer cancer deaths than would otherwise have been predicted.

Metformin and the microbiome can play well together.

“Healthy gut, healthy life,” that’s a message I’ve been delivering to my patients and readers for years. So, I’m particularly gratified by research that suggests that one way metformin improves health is through the gut microbiome. Specifically, taking the drug is associated with higher levels of a particular bacteria, Akkermansia muciniphila, which can do a number of fine things inside the gut, including helping to build up the lining of the gut wall, to prevent inflammation-promoting “leaky gut.” Some of the work has been done on animals – metformin has been shown to have an anti-inflammatory effect on mice with ulcerative colitis and, in another study, it improved cognitive performance by aged mice by reducing inflammation. In a human study, the researchers found evidence to suggest that the drug’s effect on the microbiome contributed to its ability to tamp down blood sugar levels – so there’s likely a fair amount of good news associated with this decades old medication.

Nothing is perfect.

As interesting and promising as metformin is, it does have its downsides. GI side-effects like nausea are common but for most people, they’re temporary. The drug can also interfere with the absorption of B-12. That could be more serious since B-12 levels decrease with age anyway, leaving some seniors fatigued and/or suffering from brain fog. If you’re on metformin, have your levels checked. It also may be the case that taking metformin blunts some of the body’s positive adaptation to healthier physical activity and diet, so more effort may be required to get results. However, these minor drawbacks don’t come close to off-setting the significant benefits of metformin if you’re type 2 diabetic (in which case, you’re probably already on it) and, if you’re pre-diabetic, you may want to have a conversation with your doctor about the pros and cons of metformin therapy. As for the rest of us, stay tuned.

The future of metformin.

The research that’s in the pipeline could tell us that metformin is poised to be the first all-purpose, broadly embraced anti-aging drug, which has been tested over decades, is generally well-tolerated, widely available and inexpensive. Even if the blue-sky anti-aging scenario doesn’t quite unfold, the roughly half of adult Americans who are pre-diabetic may still benefit from metformin. But the drug’s greatest contribution, as its most ardent boosters freely admit, is to open the minds of the medical establishment to the limitations of its “whack-a-mole” approach to treating disease and open the door to a new generation of anti-aging drugs that will prove to be more effective than metformin itself.

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