There may already be drugs on the market that slow down aging.
Scientists have long been interested in metformin, a widely prescribed drug for type 2 diabetes, because of its potential to slow aging. In worms, fruit flies, and rodents, the drug, which costs less than $1 per pill on average, shows promising anti-aging effects.
In a study last week, Cell Adding to the evidence that metformin can slow the passage of time, scientists gave male monkeys—the equivalent of 52 to 64 years old in human years—a daily pill for three years and monitored their physical health and cognition.
Compared with naturally aged monkeys, metformin preserved learning and memory abilities, reduced brain atrophy, and restored neurons to a younger state. The monkeys’ “brain age” was reduced by nearly 6 years, or about 18 years in human age.
Metformin’s effects extend beyond the brain. The drug reduces chronic inflammation, a hallmark of aging, in several tissues, slows liver aging, and enhances cellular mechanisms that protect the liver. The kidneys, lungs, and muscles were also “rescued” from age-related problems, with their gene expression profiles returning to younger levels.
This study fills a gap between rodents and primates. The dose of metformin given was equivalent to that used for diabetes management and may inform future clinical trials.
To be clear, this study did not investigate longevity, or how long the monkeys lived. Rather, it focused on slowing down age-related diseases, and the results contribute to our understanding of healthspan, the healthy life span that people experience.
“This study is the most quantitative and thorough examination of metformin’s action beyond mice that I’ve seen,” said Dr. Alex Soukas of Massachusetts General Hospital. natureDid not participate in the study.
Old dog, new skills
Metformin has a shiny new reputation as an anti-aging drug, but it has been around for a long time in the medical community.
Originally extracted from the root of the goat herb, a traditional European herb, researchers discovered in 1918 that it lowered blood sugar. Thirty years ago, the U.S. Food and Drug Administration (FDA) approved it for type 2 diabetes.
But metformin’s effects on the body aren’t limited to controlling blood sugar. It works through several molecular pathways to control cell growth, metabolism, and inflammation, all of which go awry during aging. This has led scientists to wonder whether the drug could slow aging.
Early studies in several animal models of aging have shown promise: Repeated doses of the drug have reversed age-related tissue damage. In humans, epidemiological studies have shown that the drug reduces the risk of cancer and dementia. A 2014 study of 78,000 people found that, on average, people with type 2 diabetes who took metformin lived longer than people of the same age who did not have diabetes and did not take the drug.
Metformin has the potential to slow age-related diseases, but it has not been directly tested in primates with this in mind.
monkey business
A new study fills that gap. The team administered metformin to crab-eating male macaque monkeys, which typically live for 25 to 30 years.
The treatment was simple. Some monkeys were given daily metformin pills, similar to the dose used to manage diabetes, at an age equivalent to about 52 to 64 years in human years. Other monkeys were allowed to age naturally without taking the drug. For comparison, the team also included young and middle-aged monkeys.
All groups underwent comprehensive physical examinations throughout the experiment, including a whopping 65 health measurements, including BMI, blood tests, and body and brain imaging.
The oldest group, who took or did not take metformin, also underwent intensive cognitive tests. Some tested their ability to remember things after a delay. Others tested how well they learned new information or updated their previous knowledge, a measure of flexible thinking that erodes with age.
The team monitored the monkeys’ health for more than three years (equivalent to about 13 years in humans), collecting samples of gene expression and protein data from multiple organs and tissues.
By comparing the metformin-treated old monkeys to young, middle-aged, and untreated old monkeys, the team came up with a “rescue score”—a measure of how much metformin slowed aging. The analysis found that the brain, skin, liver, kidneys, and lungs recovered the most.
The scientists verified their findings by looking at the tissue under a microscope. Senescent cells, often called “zombie cells,” were reduced in number. These dysfunctional cells don’t naturally replace themselves. Instead, they vomit out a soup of toxic molecules that damage surrounding tissue. Metformin also reduced the scarring that often occurs with aging, especially in the lungs, kidneys, and heart, and reduced chronic inflammation throughout the body. Inflammation is “a key hallmark of aging that underlies nearly all age-related disorders,” the team wrote.
But the most striking effect was in the brain. The monkeys given metformin maintained their learning and memory abilities as they aged. When given a variety of cognitive tests, they acted as if they were six years younger—about 20 years younger in human years—and performed significantly better mentally than their peers of similar age who were not given the drug.
Parts of the brain gradually shrink as we age. Metformin prevented shrinkage, particularly in areas important for cognition and memory, such as the front part of the brain that is important for reasoning. The drug also revived neurons in the hippocampus, a brain region involved in memory, by reducing inflammation and allowing neurons to regrow branches. Gene expression in most types of brain cells resets to a younger profile.
From rat to monkey, and then to man
Comprehensive study adds evidence to the potential anti-aging effects of metformin.
But it’s not without its flaws. The sample size is small. The study followed the aging monkeys for more than three years, but only 12 received the drug. The results, especially the “monkey aging clock,” need to be replicated in other populations.
This 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, and the biological hallmarks of aging are delayed, but their health is worse at the end of life. The aging clock is incomplete until it includes women.
The research team wants to expand the study. One idea is to follow the monkeys for longer to test whether metformin extends lifespan. Another idea is to stop the treatment to see if the anti-aging effects persist.
It is still unclear how metformin works in the aging body. Research is ongoing to elucidate the exact mechanism. However, compared to other potential longevity drugs (such as those that kill aging “zombie cells”), metformin has significant advantages. It has already been used by millions of people for decades without any major side effects.
Metformin is getting the attention of the FDA. In 2015, the FDA approved TAME, a trial to target the biology of aging. The trial aims to recruit 3,000 older adults who take metformin and those who do not, and follow them for six years. This ambitious study is still seeking sufficient funding.
Meanwhile, the authors have begun a small, placebo-controlled clinical trial to see if the drug slows aging in middle-aged to older men. Like the insights gained from the monkey study, this trial could guide strategies to delay age-related health problems.
The new study “opens the way to developing pharmacological strategies to combat human aging,” the research team wrote.
Image credit: Billy Pasco / Unsplash
