Older monkeys aged more slowly when given a cheap diabetes drug used by millions

There may already be a drug on the market that slows down aging.

Scientists have long been interested in metformin, a commonly prescribed drug to treat type 2 diabetes, because of its potential to delay aging. In worms, fruit flies and rodents, the drug — costing on average less than a dollar per pill — shows promising anti-aging effects.

Last week, a study was published in cell Further evidence that metformin can slow the passage of time: Scientists gave male monkeys aged 52 to 64 human years a pill every day for three years and monitored their physical health and cognitive abilities.

Compared to naturally aging monkeys, metformin preserved their learning and memory abilities, reduced brain shrinkage, and returned their neurons to a more youthful state. The monkeys' “brain age” was turned back by nearly 6 years, or about 18 human years.

Metformin's effects extended beyond the brain. The drug reduced chronic inflammation – a hallmark of aging – in several tissues, slowed liver aging, and strengthened the cellular mechanisms that protect the liver. Kidneys, lungs, and muscles were also “rescued” from age-related problems, with their gene expression profiles returning to more youthful ones.

The study closes the gap between rodents and primates. The doses of metformin administered were equivalent to those used to treat diabetes and could serve as a basis for future clinical trials.

To be clear, the study did not examine longevity, or how long the monkeys lived. Rather, it focused on slowing age-related diseases, with the results contributing to our understanding of healthspan—the number of healthy years of life that humans achieve.

This study is the “most quantitative and thorough investigation of the effects of metformin that I have ever seen in mice,” said Dr. Alex Soukas of Massachusetts General Hospital. Naturewho was not involved in the study.

Old dog, new tricks

Although metformin has recently gained a brilliant reputation in the fight against aging, it has been used in medicine for a long time.

Researchers found in 1918 that the plant, first extracted from goat's rue, a traditional herbal remedy in Europe, lowered blood sugar. Three decades ago, it was approved by the U.S. Food and Drug Administration (FDA) to treat type 2 diabetes.

But metformin's effects on the body go beyond regulating blood sugar levels. It works through several molecular pathways to control cell growth, metabolism and inflammation – all of which go haywire with aging. This got scientists thinking: Can the drug slow the aging process?

Initial studies on several animal models of aging were promising. Repeated doses of the drug reversed age-related tissue damage. Epidemiological studies on humans have shown that the drug reduces the risk of cancer and dementia. A 2014 study of 78,000 people showed that people with type 2 diabetes who took metformin lived longer on average than people of the same age without diabetes who did not take the drug.

Despite its potential to slow age-related diseases, metformin has not yet been directly tested in primates in this regard.

Monkey Business

The new study filled this gap. The team administered metformin to male cynomolgus monkeys, which normally have a life expectancy of about 25 to 30 years.

The treatment was simple: Some of the monkeys were given a daily metformin tablet starting at about 52 to 64 years of age, at a dosage similar to that used to treat diabetes. Others were not given the drug and were left to age naturally. For comparison, the team also included a group of young adults and a middle-aged group.

All groups underwent comprehensive physical examinations throughout the study, including a whopping 65 health measurements, such as BMI, blood tests, and imaging studies of their bodies and brains.

The oldest groups, with or without metformin, were also subjected to a barrage of cognitive tests. Some tested their ability to recall things with a delay. Others tested how well they learned new information or could update existing knowledge – a measure of flexible thinking that declines with age.

The team monitored the monkeys' health over three years – equivalent to about 13 human years – while collecting gene expression samples and protein data from multiple organs and tissues.

The team compared old monkeys treated with metformin with young, middle-aged and untreated older monkeys and determined a “rescue score” – that is, how much metformin slowed aging. The brain, skin, liver, kidneys and lungs were the most recovered, according to the analysis.

The scientists confirmed the results by examining tissue under a microscope. The number of senescent cells, often called “zombie cells,” decreased. These dysfunctional cells do not renew themselves naturally. Instead, they spit out a toxic soup of molecules that damages neighboring tissue. Metformin also reduced scarring, which often occurs during aging, particularly in the lungs, kidneys and heart, and reduced chronic inflammation throughout the body. Inflammation is a “major feature of aging that underlies nearly all age-related diseases,” the team wrote.

The most striking effect, however, was seen in the brain. Monkeys given a dose of metformin retained their learning and memory skills even as they aged. In numerous cognitive tests, they behaved as if they were six years younger – almost two decades younger than human age – and had far greater mental abilities than monkeys of the same age who had not received the drug.

Parts of the brain gradually shrink as we age. Metformin fought against this loss, especially in areas important for cognition and memory – for example, the front parts of the brain, which are crucial for logical thinking. The drug also revived neurons in the hippocampus, a brain region responsible for memory, dampened inflammation and allowed neurons to regrow their branches. Gene expression in most brain cell types was reset to a more youthful profile.

From mice to monkeys to humans

The comprehensive study provides further evidence of the potential anti-aging properties of metformin.

But it is not without its flaws. The sample size is small. Although the study followed aging monkeys for three years, only 12 received the drug. The results – particularly the “ape aging clock” – need to be reproduced in a different population.

The study also tested metformin only in men. Aging women have different trajectories on several health measures. In humans, women live longer on average than men, with delayed biological signs of aging despite being in poorer health at the end of their lives. An aging clock is incomplete unless it includes women.

The team would like to expand their study. One idea is to observe the monkeys longer to test whether metformin increases lifespan. Another idea is to stop treatment to see if the anti-aging effect lasts.

How metformin works in the aging body is currently unclear. Research is currently underway to clarify the exact mechanisms. But compared to other potential longevity drugs – such as those that kill aging “zombie cells” – metformin has one major advantage. It has been used in millions of people for decades without major side effects.

Metformin has caught the attention of the FDA. In 2015, the agency approved TAME (Targeting the Biology of Aging), a study that will recruit 3,000 older people, some taking metformin and some not, and follow them for six years. The ambitious study is still seeking sufficient funding.

The authors have since launched a smaller, placebo-controlled clinical trial to test whether the drug slows aging in middle-aged to older men. Like the findings from the monkey studies, the study could lead to strategies to slow age-related health problems.

The new study paves the way for “the further development of pharmaceutical strategies against human aging,” the team wrote.

Photo credit: Billy Pasco / Unsplash