The research on metformin and human longevity is scant, but that hasn't stopped some people from experimenting with it, and experts suggesting that a single drug that could “address everything” makes it a particularly compelling target for people eager to avoid deadly, age-related disease.
A few years ago, Marc Provissiero, a Californian in his mid-50s, started contemplating the next decades of his life. He joined a high-end longevity clinic for a few hundred dollars a month and began monitoring his blood panels, eating better and improving his sleep.
He wanted to stay active as he aged – playing tennis, surfing, hiking and spending time with his young daughter. But during Provissiero’s annual physical at the longevity clinic, his physician, Dr Darshan Shah, warned him that despite his healthy habits, his blood sugar was nearing pre-diabetic levels.
A family history heightened his risk of developing diabetes, which can shave years off a person’s life expectancy, reports The New York Times. When a stricter diet and exercise regimen didn’t move the needle, she prescribed metformin.
Scientists have known for decades that metformin lowers blood sugar. It’s approved by the Food and Drug Administration to treat type 2 diabetes and is also commonly prescribed for weight loss and polycystic ovary syndrome.
But some doctors, including Provissiero’s, are betting this same drug can head off a number of chronic diseases before they even develop, to help otherwise healthy people live longer and better.
“The hope is that this is going to lead to a greater number of healthy years,” said Provissiero, who said after one year on metformin, he feels less bloated, more energetic and more in control of his weight and blood sugar.
Research on metformin’s impact on the human lifespan is sparse.
The existing research, much of which has been done on mice, is “all over the place”, showing varying effects based on the animals’ sex and species, said Rafael de Cabo, a senior investigator at the National Institute on Ageing who has studied metformin in mice for more than two decades.
Human studies, which have largely focused on diabetes patients, turn up conflicting findings on metformin’s benefits for healthy people, he said.
Still, interest in the drug’s anti-ageing potential has remained high as scientists find early but promising evidence that it could also manage or delay other conditions like cardiovascular disease, cancer and dementia.
“Metformin may be targeting the root cause of several other diseases whose risks increase with age, potentially because it regulates hormones, repairs tissues and eases immune system inflammation,” De Cabo said.
The promise of a single drug that could “address everything” makes it especially attractive for people eager to avoid deadly, age-related disease, said Jay Olshansky, a professor of public health at the University of Illinois Chicago.
“Evidence for metformin’s ability to help humans live longer is weak, but it is not absolutely definitively negative,” added Dr Richard Miller, a professor of pathology at the University of Michigan who studies ageing.
Waiting for the big human study
Scientists are still investigating how metformin works at a molecular level. It appears to reduce cell damage by protecting chromosomes from degrading and reversing the chemical tags on DNA that are associated with ageing, among other functions, said Dr Nir Barzilai, the director of the Institute for Ageing Research at the Albert Einstein College of Medicine.
Originally derived from the French lilac plant, the drug was first formulated about 100 years ago for regulating blood sugar in animals. Doctors began offering it as a diabetes treatment to humans in the 1950s because it inhibits the body's natural production and absorption of glucose, De Cabo said.
In the early 2000s, researchers began noticing that diabetic and pre-diabetic mice who were given metformin lived longer than healthy mice who weren’t on the drug, suggesting it does more than simply treat blood sugar, De Cabo said.
For example, a 2013 study he led found that a low dose of metformin extended the lifespan of healthy male mice by about 5% (on the other hand, a higher dose shortened their lifespan). It seemed to have the same effect as caloric restriction, which the ageing field considers among the most promising possibilities for lengthening life.
A few other studies have been encouraging. One from last year suggested that metformin slowed ageing in the brain cells of male monkeys by up to six years. Another widely cited observational study in humans, published in 2014, found that people with type 2 diabetes who took metformin had a lower mortality risk than people without diabetes who didn't take it.
But other research paints a different picture. A 2022 analysis, which aimed to replicate the 2014 study, found people with diabetes taking metformin didn’t have a lower mortality risk than healthier patients who weren’t on the drug.
There’s also evidence that metformin’s benefit to people without diabetes may be short-lived, lowering their mortality risk for just a few years before it returns to normal.
A major national trial examining metformin’s impact on older healthy individuals – which could finally establish how effective the drug is at staving off chronic disease and mortality – has been delayed for years.
Called the Targeting Ageing with Metformin (or TAME) Trial, and spearheaded by Barzilai, it aims to compare the incidence of cardiovascular issues, dementia, cancer and death in people who are taking metformin with those who aren’t. But because of budget constraints and disruptions, research hasn’t begun in earnest and it will probably be years before preliminary data are published, Barzilai said.
Taking a ‘leap of faith’
There’s no reliable data on how many people use metformin strictly for longevity purposes. Some anti-ageing influencers tout metformin as part of their regimen, and doctors interviewed for this story said patients (even those without chronic disease risk) are increasingly asking them to prescribe the drug.
Though insurance doesn’t cover drugs used solely for longevity, metformin is relatively inexpensive: patients who don’t use it for chronic conditions typically pay $10 to $30 a month out of pocket.
Experts and metformin users say the drug’s risks are generally minimal; common side effects include diarrhoea and difficulty building muscle, both of which appear to abate once patients stop taking it. (Some longevity enthusiasts who were early proponents of metformin have since abandoned it, partly because of the fear of inhibiting muscle growth, which they said would outweigh the possible longevity benefits.)
More severe side effects are possible, though. De Cabo warned that the drug could compromise kidney function in patients with renal disease, if not taken under close guidance from a doctor.
Patients like Provissiero believe the potential benefits are worth the risks. Now that he’s taking metformin, he said he visits the gym more frequently to counteract any challenges building muscle, though he hasn’t experienced any issues so far.
Peter Bernard (59), said he has been taking metformin for about seven years. While he’s never struggled to keep his blood sugar low, he thought metformin could help him delay the biological breakdown that comes with age. He said there isn’t “much downside” to taking a 500mg pill twice a day, especially since he’s never noticed any negative side effects.
And although he hasn’t seen any dramatic benefits from metformin either, his blood panels and weight are consistently in the “healthy” range, and “the only way to find out if it doesn’t work is to stop”.
Proving that a drug helps people live longer could take decades, Shah said; Provissiero and other users are taking a “leap of faith” that metformin will have long-term benefits.
Even if it’s not the most powerful drug, it may well be good for people struggling to keep their blood sugar or weight within healthy guidelines, Miller said, adding that it’s “demonstrably good” at slowing the progression from pre-diabetes to diabetes.
But to anyone claiming metformin slows ageing for people “who don’t have a trace, or the least hint of pre-diabetes, I would have to say, ‘prove it’”.
It’s also difficult to determine whether the benefits are attributable to metformin alone, Miller said. Some patients who take it for longevity simultaneously take other drugs and supplements purported to slow ageing. For example, Bernard said he’s also taking testosterone, whey protein and magnesium.
And it could simply be that metformin’s biggest benefit is it triggers a change in behaviour, Provissiero acknowledged.
As he meticulously tracks his glucose and gets semi-annual lab tests for inflammation, his metformin dose is a “daily reminder” that eating healthfully and exercising can bring down his blood sugar levels, extending his life expectancy.
With lifestyle changes, he said, “I need to be a partner to it and behave.”
The New York Times article – Can Metformin Actually Slow the Ageing Process? (Restricted access)
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