Unless you’re diabetic or suffer from PCOS, you probably haven’t heard of metformin. This behind-the-scenes drug has been hailed as the “cornerstone” of Type 2 diabetes treatment for years. But outside diabetic circles, it has received very little press…until recently, that is.
In 2019, CNBC published an unusual report. Interviews with dozens of Silicon Valley techies – most of whom do not have diabetes or PCOS – revealed that the richest among us often take this 5-cent-a-pop pill for another “ailment” entirely: aging.
So, what do a centuries-old diabetes medication and the quest for eternal youth have in common?
Metformin (brand names: Fortamet, Glucophage, Glumetza, and Riomet) is an FDA-approved drug that primarily treats Type 2 diabetes. This prescription-only drug comes in both pill and liquid forms, with doses ranging from 1,000 to 2,500 milligrams per day.
Though metformin is now readily available to patients ages 10 and over, that wasn’t always the case. In fact, as recently as the 1980s, the FDA staunchly declared that metformin would “never” be approved in the United States.
To understand why, let’s take a brief trip down memory lane.
Metformin, much like aspirin or THC, has been used in plant form for hundreds of years.
In medieval Europe, the medicinal herb Galega officinalis was a popular treatment for frequent urination. (We now know that frequent urination is an indicator of diabetes.) The plant went by different names around the world, including French lilac, false indigo, and Spanish sainfoin.
In the 1800s, the plant’s active ingredient, guanidine, was isolated for the first time, and synthesized into a less-toxic compound in the early 1920s. From this research arose two drugs: metformin and phenformin.
For a few years, both drugs enjoyed notoriety as groundbreaking diabetes treatments. But their fame soon turned to infamy, as a startlingly high number of phenformin patients developed lactic acidosis, a potentially fatal condition wherein the body accumulates lactic acid in the blood. As a result, both drugs were pulled off the market.
But by the 1950s, Europe once again approved metformin for diabetes treatment. (Unlike phenformin, metformin only rarely causes serious side effects.) The U.S. FDA was far warier, vowing in the 1980s to “never” approve its use again. But public and scientific opinion pushed back as more use cases poured out of Europe. Finally, in 1995, the FDA approved metformin for Type 2 diabetes patients once more.
However, ongoing research suggests that metformin’s benefits may extend far beyond the realm of diabetes.
Metformin is an unusual drug because it helps lower high blood sugar without altering insulin production or triggering hypoglycemia. (Because it doesn’t affect insulin production, it’s not prescribed for insulin-dependent diabetics.) Moreover, it’s less likely to cause weight gain than other treatments, making it a prime candidate for individuals who struggle with weight loss.
While metformin’s mechanisms aren’t fully understood, evidence suggests that metformin acts via three primary pathways:
• Increasing insulin sensitivity. Insulin is a hormone that moves sugar around the body. If you have too much sugar in your blood, insulin becomes less effective, leading to even bigger sugar buildups. Metformin decreases this insulin resistance, allowing your body to use and absorb sugar more effectively.
• Lowering sugar absorption. Most sugar enters the body through our diets. When food reaches your intestines, your body pulls sugar into your bloodstream. Metformin limits this process, decreasing the amount of sugar absorbed.
• Lowering sugar production. Simultaneously, metformin also decreases the amount of sugar that your liver naturally produces. In turn, this further lowers the amount of sugar in your bloodstream, contributing to increased insulin sensitivity.
Like any drug, metformin can potentially cause side effects. The most common ones are stomach problems, including gas, nausea and vomiting, diarrhea, and cramping.
Fortunately, these tend to be relatively mild, and may subside as your body adjusts to the medication. Many healthcare providers also stair-step up metformin doses, slowly increasing to a maximum of 2,500 milligrams per day.
However, some populations are ill-suited for metformin due to underlying risk factors. For example, those at risk of severe kidney disease, metabolic acidosis, or diabetic ketoacidosis generally shouldn’t take metformin.
Due to its solid safety profile and low cost (around $5 per month), metformin makes an ideal candidate for Type 2 diabetes treatment. But thanks to a host of chemical mechanisms we don’t wholly understand, metformin’s uses aren’t limited to Type 2 diabetes.
For example, metformin is often prescribed off-label to treat non-insulin-dependent diabetes like pre-diabetes and gestational diabetes. Women with PCOS (polycystic ovarian syndrome) may also take metformin to modulate insulin sensitivity, weight loss, and fertility.
And thanks to its weight loss potential, some doctors use metformin to mitigate weight gain in individuals taking certain antipsychotics.
However, these are just metformin’s generally accepted uses. In recent decades, scientists have become increasingly intrigued by data coming out of studies on Type 2 diabetics and metformin. In particular, research has shown that metformin may have a number of positive – but unintended – consequences.
Until recently, the FDA has been reticent to approve metformin for large-scale studies outside the diabetic population. But within this population, scientists have discovered that metformin may:
• Lower death rates due to cardiovascular disease • Lower dementia and stroke risks • Decrease the risk of (or even help treat) certain cancers, particularly reproductive, colorectal, and prostate cancers • Increase male and female fertility, even with sperm frozen outside the body • Improve outcomes for those with nonalcoholic fatty liver disease and HIV-related lipodystrophy
While we don’t fully understand the mechanisms behind these effects, it’s clear from preliminary research that metformin shows promise. And metformin doesn’t just treat these diseases – it may also increase life expectancy in diabetic and non-diabetic populations, too.
Currently, there’s little human research outside the diabetic population on metformin’s effects on aging. But several animal models suggest that mice that take metformin have both prolonged lifespans and health span. (Your health span measures how many of your years are healthy and relatively disease-free.)
Additionally, one small human trial found that metformin may cause changes in bodily processes that protect against aging. And while we can’t pinpoint why, metformin shows a range of unintended and indirect effects that target the aging process, including:
• Boosting cellular metabolism • Reducing oxidative stress • Protecting vascular (blood vessel) function • Boosting cellular health in organ linings
Some research also indicates that metformin’s ability to modulate blood sugar and insulin receptivity contributes to several benefits. For example, it’s well-known that sugar can cause inflammation – and metformin is thought to lower inflammation via hypoglycemic pathways.
Moreover, it’s thought that high insulin levels may promote cancer. Because metformin modulates insulin (and other hormones), it’s possible that the reason metformin is great for diabetics is what gives it such great anti-cancer potential.
One of metformin’s most ardent supporters is an endocrinologist by the name of Dr. Nir Barzilai, MD. As director of the Institute for Aging Research at the Albert Einstein College of Medicine, he’s spent his life seeking to counteract the effects of aging on the body. And now, he’s heading an unprecedented research trial to prove that metformin may just be an anti-aging miracle drug.
Starting in the 1980s, researchers discovered something striking. When comparing diabetics who took metformin to diabetics on other drugs, the metformin-taking population:
• Lived longer • Suffered fewer cardiovascular events • Was less likely to suffer dementia and Alzheimer’s • Got cancer 25-40% less often than other diabetic populations • Outlived diabetics with cancer on other medications
Additionally, later research from 2014 found that in a study of 90,400 Type 2 diabetics, metformin was more likely to help diabetics live longer. And that was true not only compared to individuals on other anti-diabetic medications, but also nondiabetics who didn’t take the drug.
It was this research that inspired Dr. Barzilai to look into metformin’s anti-aging potential. Unfortunately, until recently, the FDA didn’t recognize “aging” as a medical condition to treat. And even if they had, there’s still the problem of demonstrating how aging slows.
Armed with information from prior research studies, Dr. Barzilai persuaded the FDA to greenlight a massive study – and the first of its kind. The study, dubbed TAME (Targeting Aging with Metformin), collected 3,000 people aged 65-79 to look at metformin’s effects on the aging process, including its:
• Cognitive effects • Cardiovascular potential • Anti-cancer properties
Through TAME, Dr. Barzilai hopes to demonstrate that metformin usage can delay the onset of age-related diseases. And while he believes metformin could extend an individual’s lifespan, for him, that’s not the ultimate goal. Instead, he hopes to improve people’s quality of life as they enjoy their golden years.
Dr. Barzilai’s research hasn’t yet concluded, so the jury is still out on metformin as an anti-aging miracle. That said, multiple smaller, tangential studies suggest that metformin’s potential extends far beyond the realm of Type 2 diabetes.
And though it shows significant anti-cancer, pro-cognition, pro-cardiovascular effects – all of which are crucial to the anti-aging formula – no one quite understands why.
Fortunately, current and future studies plan to examine these potential benefits in full. And while those outside Silicon Valley require a doctor’s prescription to enjoy these benefits, Nir Barzilai hopes to change that soon.
Defining Chronological and Biological Age
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