Metformin May Be a Potential Wonder Drug for Healthy Ageing

A widely used medicine prescribed to patients since the 1950s could have transformative implications for human health, according to researchers.

In a recent review, scientists even describe it as a possible "wonder drug", while stressing that further work is required to establish how it could serve modern medicine - particularly its potential to slow biological ageing.

The medicine is metformin, a first-line treatment for type 2 diabetes that is included on the World Health Organization's Essential Medicines list.

Although scientists first synthesised it more than a century ago and it has long ranked among the most frequently prescribed drugs in the US, metformin still holds surprises for doctors and researchers.

In fact, it does not appear that everything about metformin is yet understood.

A rising body of evidence in recent years indicates that the medicine's full potential remains unexplored, as researchers uncover ways in which metformin operates that had not previously been recognised.

Most significantly, research suggests metformin could possess substantial anti-ageing effects in both people and animals. However, scientists are only beginning to work out how the drug may produce these outcomes.

How metformin may influence biological ageing

In a paper published in Aging, researchers assess the current understanding of metformin and consider the mechanisms behind its possible anti-ageing and longevity-enhancing effects.

"Apart from its primary role in lowering blood glucose levels, metformin has been shown to have several effects at the molecular level," the research team, led by first author and genomics researcher Jarra Manneh from Hamad Bin Khalifa University in Qatar, explains in their study.

Among its key actions is the activation of AMP-activated protein kinase (AMPK), an enzyme found within cells.

As well as helping to reduce blood glucose, this activation can have several other consequences. These include suppressing a protein kinase called mTOR, increasing autophagy - the cellular process of recycling damaged or unneeded components - lowering oxidative stress, and enhancing insulin sensitivity.

Together, these mechanisms may slow cellular ageing and could potentially extend longevity in animals.

Although the equivalent pathway in humans is still largely theoretical, elevated AMPK levels have been shown to lengthen worms' lifespans. By contrast, removing the enzyme in mice reduces their lifespan.

Metformin might also delay ageing through epigenetic changes connected with metabolism, inflammation and ageing. This includes altering the production of the enzyme ten-eleven translocation 2 (TET2).

"Increased TET2 stability induced by metformin intake leads to lower abnormal methylation patterns that result in genomic instability during the aging process," the researchers write.

"This decrease in abnormal DNA methylation patterns results to better genomic stability and prevents the risk of age-related diseases thereby maintaining a methylation profile that remains youthful."

A noteworthy 2022 study reported that, among people with type 2 diabetes, taking metformin was associated with epigenetic signs of slower ageing than in those who did not take the drug.

The observed difference equated to 2.7–3.4 years less biological ageing. Nevertheless, the research involved only 32 patients, meaning it was a small study, and it did not prove that metformin caused the changes recorded.

Metformin is also believed to offer geroprotective effects through its influence on gut bacteria. By changing the gut microbiome, it may reduce inflammation, reinforce intestinal integrity and improve metabolic health.

In an experiment reported in 2022, mice on a high-fat diet that received metformin showed reduced tumour growth, an effect thought to result from microbiome changes.

Evidence for metformin and longevity remains limited

Despite the vast amount of research into metformin and its many potential longevity-promoting mechanisms, Manneh and colleagues emphasise that large-scale, conclusive evidence of its effect on human longevity is not yet available. Most studies to date have either been observational or carried out in animals.

Many human studies have chiefly examined metformin in relation to particular diseases. Despite considerable circumstantial evidence from other research areas, this makes it difficult to isolate a single geroprotective effect in healthy people.

"Most of these studies had heterogeneous endpoints (mortality, cancer incidence, cardiovascular events, frailty-related, biological aging markers) usually combined under aging," the researchers write.

"While this broad scope is conceptually useful, it makes it difficult to determine if metformin improves healthspan or just affects selected disease outcomes in selected populations."

Even so, there are encouraging indications ahead.

A forthcoming major study, Targeting Aging with Metformin (TAME), aims to assess the medicine's effects in around 3,000 participants through clinical trials conducted at 14 US research institutions over six years.

Should TAME or other clinical trials proceed, they may at last provide robust evidence to support the many promising signs identified so far.

For now, metformin's full capacity to ease the effects of passing time has not been realised.

"More research, especially randomized clinical trials in non-diabetic populations, are needed to investigate the drug's epigenetic and microbiome-mediated effects as well as develop predictive aging biomarkers reactive to metformin," the researchers write.

"By merging data from clinical, molecular and population level, metformin could be the wonder drug that redefines the limits of healthy aging."

The findings are reported in Aging.

This article was fact-checked by Clare Watson and edited by Clare Watson. Although we take pride in our process, we are only human. If you notice an error, please let us know.