Why do some researchers believe metformin may hold the key to longevity?

Metformin is an oral prescription drug widely used to control blood sugar in type 2 diabetes. Recently, studies have found several other potential health benefits of the drug, including fighting cancer and obesity, and improving the health of people with liver, kidney, and cardiovascular diseases. Now, some experts suggest that it may increase healthy life years, and even extend lifespan. This Special Feature looks at how metformin might boost the health span, and asks whether it truly has potential as an anti-aging treatment.

Type 2 diabetes affects more than 6% of the world’s population — around 462 million people. It occurs when a person stops responding correctly to insulin, the hormone produced by the pancreas that controls blood glucose (sugar) levels.

A person with type 2 diabetes will have raised blood glucose, which leads to symptoms including frequent urination, extreme thirst, weight loss, fatigue, blurred vision, infection and sores. Without treatment, raised blood glucose can lead to life-threatening health complications.

Metformin was approved by the Food and Drug Administration (FDA) in 1994 to treat raised blood glucose in people with type 2 diabetes. When combined with diet and exercise, it is an effective way of controlling blood sugar levels.

People take metformin as an oral tablet. There are two types — immediate release, which are generally taken twice a day, and extended release, which people take once daily. People usually start on a dose of 500 milligrams (mg) a day, up to a maximum of more than 2,000 mg a day if needed to keep blood sugar under control.

During treatment with metformin, a person’s clinician will regularly check their blood glucose levels, glycosylated hemoglobin (A1C) levels (a measure of long-term blood glucose control), cholesterol, vitamin B12 levels, and kidney function.

How does metformin work?

Metformin belongs to a class of drugs called biguanides, which have been used for more than 70 years for the treatment of type 2 diabetes.

It works by helping the body respond to insulin, and by decreasing the amount of sugar that the liver produces and that the intestines or stomach absorb. However, the exact mechanisms by which it has these effects are still unclear.

Although primarily a treatment for type 2 diabetes, metformin is also used to manage polycystic ovary syndrome (PCOS), a hormonal disorder that affects up to 20% of women. In PCOS, metformin reduces high insulin levels to help regulate reproductive hormones and relieve symptoms.

Studies have suggested that metformin has other health effects. These may include anti-cancer properties, combating obesity, helping protect the cardiovascular and nervous system, and even anti-aging effects.

It is these anti-aging effects that have prompted increasing interest and led to a trial being set up by the American Federation for Aging Research.

The Targeting Aging with Metformin (TAME) Trial will enroll more than 3,000 individuals aged between 65 and 79 in a series of nationwide, six-year clinical trials at 14 leading research institutions across the United States.

The trials will test whether metformin delays development or progression of age-related chronic diseases—such as heart disease, cancer, and dementia.

Could metformin prolong healthy life?

With an aging population worldwide, age-related diseases are becoming one of the greatest challenges, and costs, facing health care.

Although lifespans have been increasing, health spans have not, with many older adults experiencing multiple chronic diseases. So anything that can prolong the years of healthy life and minimize the time people spend with chronic conditions would benefit both individuals and healthcare systems.

Although some factors, such as genetics, are beyond our control, the National Institute on Aging advises the following to help you remain healthy into older age:

• stay active — regular exercise not only helps you live longer, but helps delay the chronic conditions of old age
• follow a healthy diet, including lots of fresh fruits and vegetables, whole grains, healthy fats, and lean proteins, such as the Mediterranean diet
• get a good night’s sleep, aiming for 7–9 hours a night
• give up smoking if you are a smoker
• avoid or limit alcohol consumption
• get regular health screenings.

But should taking metformin be added to that list?

Metformin’s anti-aging effects

Some studies in animals have suggested that metformin can increase lifespan.

In nematode worms, Caenorhabdytis elegans, metformin given at 25, 50 and 100 millimoles (mM) concentration increased mean lifespan by 18%, 36% and 3%.

In mice, metformin at 0.1% wet weight in diet starting in middle age increased both lifespan and healthspan, but a higher dose (1% wet weight) was toxic. The effect seen in this study was similar to that of caloric restriction.

In another study, metformin increased mean lifespan by 14% in female mice if started at 3 months. When metformin treatment was started later, the effect was much smaller, starting at 9 months increased lifespan by 6%, and at 15 months, there was no increase. The drug also increased reproductive function and delayed tumor development.

However, in another study, in fruit flies, Drosopholila melanogaster, researchers found that metformin did not extend lifespan in male or female flies, and was toxic at higher doses.

In people, studies have shown that metformin improves age-related diseases, such as type 2 diabetes, cardiovascular disease and cognitive issues, which may lead to extended lifespan.

David Merrill, MD, PhD, geriatric psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center at Providence Saint John’s Health Center in Santa Monica, CA, explained to Medical News Today:

“Metformin certainly lessens complications of type 2 diabetes, especially when combined with healthy carb-controlled diet and regular physical exercise. This will help reach the goal of aging without chronic disease or disability.”

How might metformin work to boost health span?

“Metformin improves insulin sensitivity, promotes cellular repair, is anti-inflammatory, and antioxidant. All these properties contribute to its anti-aging effects,” Merrill told us.

Studies in people with type 2 diabetes have shown that metformin activates the AMP-activated protein kinase (AMPK). It also activates autophagy — the process of cell recycling. Both of these might explain some of its anti-aging properties.

Sebnem Unluisler, chief longevity officer and genetic Engineer at the London Regenerative Institute, in the United Kingdom, explained that “[m]etformin’s potential mechanisms for anti-aging effects encompass its ability to influence critical processes associated with aging.”

“These include regulating nutrient sensing, maintaining proteostasis, improving mitochondrial function, modulating intercellular communication, preserving telomere length, stabilizing the genome, impacting epigenetic modifications, attenuating stem cell depletion, and reducing cellular senescence,” she added.

Oxidative stress is involved in several age-related conditions, including cardiovascular diseases, chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases, cancer, sarcopenia (muscle loss) and frailty.

And oxidative stress can be a direct result of poor blood sugar control, resulting in the production of excess free radicals — unstable, highly reactive molecules that damage cells and DNA.

So, by controlling blood sugar, metformin helps prevent production of excess free radicals, thereby reducing oxidative stress and the age-related conditions it can cause.

“By targeting these pathways, metformin has the potential to delay the onset or progression of age-related chronic diseases, including heart disease, cancer, and dementia.These mechanisms may contribute to its observed benefits beyond glycemic control,” Unluisler explained.

Might metformin help you look younger?

Tunc Tiryaki, board-certified plastic surgeon, founder of the Tiryaki Clinic in Istanbul and a consultant plastic surgeon at Cadogan Clinic in London, suggested that metformin might have other beneficial effects, too.

“Metformin, a widely used medication for managing type 2 diabetes, has shown promising potential beyond glycemic control, possibly extending to facial bone and skin aging. Metformin’s mechanisms, such as stimulating bone formation and reducing resorption, offers the potential for maintaining facial bone density,” he told us.

“As facial bones support the skin structure, this could translate to improved facial contours and reduced signs of aging,” he added.

“However,“ Tiryaki cautioned, “further studies are required to fully elucidate metformin’s specific effects on facial bone health and its potential as an anti-aging intervention.”

A potential low-cost anti-aging treatment?

The TAME trial wants to investigate whether metformin might work by targeting overall aging, instead of treating age-related diseases individually. If the trial shows that it does have anti-aging effects, the organizers hope to gain FDA approval for the drug as an ‘indication’ for aging.

This would mean metformin could be prescribed to treat aging in people without type 2 diabetes, rather than just for type 2 diabetes and other indicated conditions, such as PCOS.

However, Merrill cautioned that its use could have unwanted effects. “[N]o medications are without potential side effects,“ he said.

Some of the side effects linked to metformin use include “stomach upset, nausea, or diarrhea,” noted Merrill.

Unluisler, nevertheless, welcomed the trial, telling us that “[i]f TAME and similar trials demonstrate positive outcomes, metformin could potentially become a groundbreaking intervention for promoting healthy aging and reducing the burden of age-related diseases.”

And Merrill added that, when used under the supervision of a prescribing doctor: “Metformin may be a lower cost way to help older aged individuals remain healthy for longer. It’s an important quality of life question worth studying.”

https://www.medicalnewstoday.com/articles/why-do-some-researchers-believe-metformin-may-hold-the-key-to-longevity#Might-metformin-help-you-look-younger?