Arguing for Metformin's Effects on Life Expectancy to be Due to Suppression of Excessive Inflammation
Researchers have been arguing for some years now that metformin improves life span via suppression of excessive inflammation. Metformin, it has to be said, has terrible, unreliable, very mixed animal data when it comes to slowing aging. Plus that one human study in diabetic patients in which life expectancy was very modestly increased. So it seems to me that progress in understanding what is going on under the hood is largely of academic interest at this point in time. The effect size is just not large enough to be a medical focus. If suppression of inflammation and extended healthy lives are the goals on the table, then senolytic therapies to clear out senescent cells and their inflammatory signaling look much more promising.
Metformin is a widely prescribed blood sugar-lowering drug. It is often used as an early therapy (in combination with diet and lifestyle changes) for type 2 diabetes. Metformin works by lowering glucose production in the liver, reducing blood glucose levels that, in turn, improve the body's response to insulin. But scientists have also noted that metformin possesses anti-inflammatory properties, though the basis for this activity was not known. Researchers have now identified the molecular mechanism for the anti-inflammatory activity of metformin and, in mouse studies, found that metformin prevents pulmonary or lung inflammation in animals infected with SARS-CoV-2, the virus that causes COVID-19.
But while clinical studies suggested metformin's anti-inflammatory activity, rather than lowering of blood glucose, could be responsible for reduced COVID-19 severity and mortality, none of the studies offered an explanation or prompted large, randomized clinical trials needed for obtaining conclusive answers.
IL-1β, along with IL-6, are small proteins called cytokines that cause inflammation as an early immune response. Their amounts are often highly elevated in persons infected by SARS-CoV-2, creating "cytokine storms" in which the body starts attacking its own cells and tissues. They are signs of an acute immune response gone awry. Production of IL-1β depends on a large protein complex called the inflammasome.
Researchers confirmed that metformin inhibited inflammasome activation and prevented SARS-CoV-2-induced pulmonary inflammation in mice. Cell culture studies using macrophages revealed the underlying mechanism by which metformin exerts its anti-inflammatory activity: reduced production of ATP by mitochondria. ATP is the molecule that mitochondria use to store chemical energy for cells. It is essential to all cellular processes, but blunted ATP production in liver cells is responsible for the glucose lowering effect of metformin.
Lower amounts of ATP in macrophages led to inhibition of mitochondrial DNA synthesis, a critical step in NLRP3 inflammasome activation. Subsequent research found that clearing away damaged mitochondria reduced NLRP3 inflammasome activity and reduced inflammation. "These experiments strongly suggest that improved delivery of metformin into lung macrophages can provide new treatments for severe COVID-19. The findings suggest metformin may have therapeutic potential for treating a variety of neurodegenerative and cardiovascular diseases in which NLRP3 inflammasome activation is a factor. Inhibition of inflammasome activation may also account for the poorly explained anti-aging effect of metformin."
Link: https://www.eurekalert.org/pub_releases/2021-06/uoc--cdd060821.php