Does Metformin Work as a Life-Extension Drug?

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Amazingly, diabetics placed on metformin may live longer lives than those who never got diabetes in the first place.

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Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.

Intro: Might the diabetes drug, Metformin, have an anti-aging effect? Check out this three-video series to see what the science says.

The noxious weed goat’s rue was widely used as herbal medicine back in the Middle Ages for thirst and frequent urination, what we now know as a cardinal symptom and sign of diabetes. The plant produces a mitochondrial poison known as galegine. One can imagine how this could help discourage grazing herbivores, but why would crippling mitochondrial function help with diabetes? If you got the dose just right, you could impair energy production just enough to spring AMPK into action. AMPK would then dial down the liver’s energy-intensive process of sugar production, and blood sugars would fall.

Galegine proved too toxic for use in humans (and presumably goats), but was tweaked into a milder form in the 1950s. That’s the origin story of metformin––now, even 60+ years later, the most widely prescribed diabetes drug in the world. Sold originally as Glucophage (meaning “sugar eater”), metformin is now prescribed annually more than 90 million times in the U.S. alone. Despite all the strides in biotechnology, Big Pharma has yet to come up with a safer, more effective first-line treatment for type 2 diabetes than a drug that retails at pennies per pill.

Ramping up AMPK isn’t all that metformin does (for example, it also appears to foster the growth of good bacteria in the gut). But, the AMPK boost alone would be expected to have wide-ranging health effects. Remember, AMPK is activated when resources are scarce. So, it causes the body to hunker down into energy-conservation mode, and put the brakes on new construction projects. So, no more making excess blood sugar or cholesterol. Time to start tapping into the larder. And, indeed, metformin doesn’t just lower sugars in the blood, but cholesterol and body fat. And, shutting down the excess synthesis of proteins can also have health benefits.

Fibrosis is the accumulation of scar tissue in response to an inflammatory insult. As a transient, localized phenomenon, fibrosis helps heal wounds and repair damaged tissue. But in response to the systemic inflammation of aging, surplus scar tissue can build up in our heart, liver, kidneys, and lungs. Excess fibrosis is estimated to contribute to 45 percent of all deaths in the United States. But AMPK switches the body into miser mode, shrinking the energy budget for such superfluous activities, and ratchets down fibrotic processes.

The AMPK priorities shift from growth to preservation might also be expected to slow cancer progression. Based on dozens of observational studies involving tens of thousands of diabetic cancer patients, those on metformin did indeed experience a significant survival advantage, correlating with a 26 percent decreased risk of dying from cancer. No wonder there are more than 100 ongoing studies to put metformin to the test against cancer. As the director of Harvard’s Cancer Center put it, “Metformin may have already saved more people from cancer deaths than any drug in history.”

If AMPK plays such a key role in the aging process, and metformin boosts AMPK, can metformin slow aging and lengthen lifespans? It certainly can in some species. C. elegans worms fed metformin maintain a youthful state, and can exhibit a nearly 40 percent increase in average survival. Interfere with the AMPK pathway, though, and this lifespan extension disappears, confirming the role of AMPK in metformin’s anti-aging effects. Metformin also improves the healthspans and lifespans of mice, but failed to extend the lives of rats, calling the pro-longevity effects of metformin into question.

The dose they used (15 times that used in humans) may have been too high, however, and the F344 rats they used are an inbred strain (named after the 344th brother–sister mating) that are resistant to the health benefits of calorie restriction. Since metformin acts through AMPK as a calorie restriction mimetic, it stands to reason that these animals may be less prone to metformin’s effects. What about humans?

Unlike other potential anti-aging drugs in the pipeline, we have the benefit of data on more than a million study subjects who have been tracked in metformin trials. And, indeed, compared to diabetics who take drugs other than metformin, those on metformin appear protected from age-related susceptibilities like fractures or serious infection, glaucoma, and cognitive impairment.

Most importantly, diabetics who take metformin live significantly longer than those taking different sugar-lowering drugs. Doesn’t that prove metformin is a pro-longevity drug? No. For example, maybe metformin just controlled their diabetes better. Researchers still found a survival benefit for diabetics on metformin compared to those as well managed on other drugs, but maybe the other drugs were shortening lifespans, and so, metformin just looked good in comparison. How could you try to tease out the effects?

What if you compared the lifespans of diabetics on metformin to nondiabetics? Now, that’s not really a fair comparison. Any benefits metformin has could easily be outweighed and masked by the life-limiting nature of diabetes—unless, that is, the diabetics on metformin actually lived longer. Longer than nondiabetics. And, are you sitting down? That’s exactly what the research shows. Diabetics placed on metformin went on to live longer lives than those who never got diabetes in the first place. From a longevity standpoint, it’s as if they got lucky to be diagnosed with diabetes, because then, they had access to this lifespan-enhancing drug. So, wait. If metformin is so powerful as to more than offset such a dreaded diagnosis, should everyone be taking metformin? What are the downsides? That’s exactly what I’m going to be covering next.

Please consider volunteering to help out on the site.

Motion graphics by Avo Media

Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.

Intro: Might the diabetes drug, Metformin, have an anti-aging effect? Check out this three-video series to see what the science says.

The noxious weed goat’s rue was widely used as herbal medicine back in the Middle Ages for thirst and frequent urination, what we now know as a cardinal symptom and sign of diabetes. The plant produces a mitochondrial poison known as galegine. One can imagine how this could help discourage grazing herbivores, but why would crippling mitochondrial function help with diabetes? If you got the dose just right, you could impair energy production just enough to spring AMPK into action. AMPK would then dial down the liver’s energy-intensive process of sugar production, and blood sugars would fall.

Galegine proved too toxic for use in humans (and presumably goats), but was tweaked into a milder form in the 1950s. That’s the origin story of metformin––now, even 60+ years later, the most widely prescribed diabetes drug in the world. Sold originally as Glucophage (meaning “sugar eater”), metformin is now prescribed annually more than 90 million times in the U.S. alone. Despite all the strides in biotechnology, Big Pharma has yet to come up with a safer, more effective first-line treatment for type 2 diabetes than a drug that retails at pennies per pill.

Ramping up AMPK isn’t all that metformin does (for example, it also appears to foster the growth of good bacteria in the gut). But, the AMPK boost alone would be expected to have wide-ranging health effects. Remember, AMPK is activated when resources are scarce. So, it causes the body to hunker down into energy-conservation mode, and put the brakes on new construction projects. So, no more making excess blood sugar or cholesterol. Time to start tapping into the larder. And, indeed, metformin doesn’t just lower sugars in the blood, but cholesterol and body fat. And, shutting down the excess synthesis of proteins can also have health benefits.

Fibrosis is the accumulation of scar tissue in response to an inflammatory insult. As a transient, localized phenomenon, fibrosis helps heal wounds and repair damaged tissue. But in response to the systemic inflammation of aging, surplus scar tissue can build up in our heart, liver, kidneys, and lungs. Excess fibrosis is estimated to contribute to 45 percent of all deaths in the United States. But AMPK switches the body into miser mode, shrinking the energy budget for such superfluous activities, and ratchets down fibrotic processes.

The AMPK priorities shift from growth to preservation might also be expected to slow cancer progression. Based on dozens of observational studies involving tens of thousands of diabetic cancer patients, those on metformin did indeed experience a significant survival advantage, correlating with a 26 percent decreased risk of dying from cancer. No wonder there are more than 100 ongoing studies to put metformin to the test against cancer. As the director of Harvard’s Cancer Center put it, “Metformin may have already saved more people from cancer deaths than any drug in history.”

If AMPK plays such a key role in the aging process, and metformin boosts AMPK, can metformin slow aging and lengthen lifespans? It certainly can in some species. C. elegans worms fed metformin maintain a youthful state, and can exhibit a nearly 40 percent increase in average survival. Interfere with the AMPK pathway, though, and this lifespan extension disappears, confirming the role of AMPK in metformin’s anti-aging effects. Metformin also improves the healthspans and lifespans of mice, but failed to extend the lives of rats, calling the pro-longevity effects of metformin into question.

The dose they used (15 times that used in humans) may have been too high, however, and the F344 rats they used are an inbred strain (named after the 344th brother–sister mating) that are resistant to the health benefits of calorie restriction. Since metformin acts through AMPK as a calorie restriction mimetic, it stands to reason that these animals may be less prone to metformin’s effects. What about humans?

Unlike other potential anti-aging drugs in the pipeline, we have the benefit of data on more than a million study subjects who have been tracked in metformin trials. And, indeed, compared to diabetics who take drugs other than metformin, those on metformin appear protected from age-related susceptibilities like fractures or serious infection, glaucoma, and cognitive impairment.

Most importantly, diabetics who take metformin live significantly longer than those taking different sugar-lowering drugs. Doesn’t that prove metformin is a pro-longevity drug? No. For example, maybe metformin just controlled their diabetes better. Researchers still found a survival benefit for diabetics on metformin compared to those as well managed on other drugs, but maybe the other drugs were shortening lifespans, and so, metformin just looked good in comparison. How could you try to tease out the effects?

What if you compared the lifespans of diabetics on metformin to nondiabetics? Now, that’s not really a fair comparison. Any benefits metformin has could easily be outweighed and masked by the life-limiting nature of diabetes—unless, that is, the diabetics on metformin actually lived longer. Longer than nondiabetics. And, are you sitting down? That’s exactly what the research shows. Diabetics placed on metformin went on to live longer lives than those who never got diabetes in the first place. From a longevity standpoint, it’s as if they got lucky to be diagnosed with diabetes, because then, they had access to this lifespan-enhancing drug. So, wait. If metformin is so powerful as to more than offset such a dreaded diagnosis, should everyone be taking metformin? What are the downsides? That’s exactly what I’m going to be covering next.

Please consider volunteering to help out on the site.

Motion graphics by Avo Media

Doctor's Note

This is the third video in a five-part series. If you missed the first two, see Naturally Boosting AMPK with Caloric Restriction for Life Extension and Naturally Boosting AMPK with Exercise for Life Extension.

Stay tuned for Side Effects of Metformin as a Life-Extension Drug and The TAME Trial: Targeting Aging with Metformin.

AMPK is one of the anti-aging pathways I highlight in my longevity book, How Not to Age, available in print, e-book, and audio. (All proceeds I receive from the book are donated directly to charity.)

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