Metformin, a safe and inexpensive drug used to treat type 2 diabetes, decreases the risk of heart attacks and strokes triggered by air pollution.
It works by reducing inflammation in the lungs that triggers clotting, according to a new study.
Metformin flips a switch in immune cells that reside in the lung and continuously samples the air we breathe. It prevents those immune cells, known as macrophages, from releasing dangerous molecules into the blood that promote heart attacks and strokes after pollution exposure.
“These findings suggest metformin as a potential therapy to prevent some of the premature deaths attributable to air pollution exposure worldwide,” says co-lead author Scott Budinger, professor of airway diseases and chief of pulmonary and critical care at Northwestern University Feinberg School of Medicine. Budinger is also a Northwestern Medicine pulmonary and critical care physician and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
More than 100 million people take metformin worldwide. The drug works by targeting the mitochondria—the cell’s energy center—in lung macrophages. When air pollution particles get into the lungs, the mitochondria release hydrogen peroxide that promotes inflammation and clotting. Metformin slows down the mitochondria and the release of hydrogen peroxide.
“The simplest next step would be to validate our study with metformin in people in China or other places where exposure to high levels of air pollution are common to see if it reduces inflammation,” Budinger says
China and India
Air pollution remains an enormous US public health problem, causing thousands of excess deaths in the Medicare population alone each year. The large majority of these deaths are due to heart attacks and strokes.
Because air pollution levels are about 10 times higher in China, India, and other parts of the developing world compared to the US, the global health impact of air pollution is much larger, Budinger notes.
In the study, which appears in Cell Press, a pediatric formulation of metformin was given to mice in their drinking water for three days. It was an equivalent concentration to the dose people take for diabetes. Mice were exposed to air pollution from Chicago in a specially designed chamber that concentrates the particles to levels similar to those seen in China.
When mice were exposed to air pollution in the laboratory, their macrophages released an inflammatory molecule called IL-6, which has been linked to heart attacks and strokes. Metformin prevented the release of IL-6 and reduced the speed at which clots formed after an injury. The same findings were seen in lung macrophages from humans.
“We know it’s an anti-diabetic drug, it can be an anti-cancer drug, and now our study suggests it’s a reasonable anti-inflammatory drug.”
The findings are a result of Budinger’s more than 20-year collaboration with Northwestern
scientist Navdeep Chandel, who studies metformin and its effects on mitochondrial metabolism.
Three years ago, Chandel, professor of medicine & cell biology, showed how metformin inhibits cancer progression. Studies had shown that the drug prevented cancer progression, but scientists didn’t fully understand how it worked. The researchers discovered that metformin slows mitochondrial metabolism to prevent the growth of cancer.
Slow down aging?
To prove that targeting the mitochondria in macrophages could prevent inflammation in response to pollution, Budinger and Chandel created mice where lung macrophages lacked key mitochondrial proteins.
Like the mice treated with metformin, these mice were protected against pollution-induced inflammation. These results suggest that “metformin is a pharmacological way of doing the same thing,” Chandel says.
“We know it’s an anti-diabetic drug, it can be an anti-cancer drug, and now our study suggests it’s a reasonable anti-inflammatory drug.”
Now, the Chandel and Budinger labs are determining whether metformin can target mitochondrial metabolism to prevent or slow aging and age-related diseases including diabetes, inflammation, cancer, and neurodegeneration. In parallel, other scientists are planning to give metformin to people older than 65 to see if it can delay the onset of aging-related diseases in the Targeting Aging with Metformin (TAME) trial.
Other coauthors are from Northwestern and the University of Chicago. The National Institutes of Health, the Veterans Administration, and the US Department of Defense funded the work.
Source: Northwestern University
