Fibrosis is a form of malfunction in tissue maintenance and regeneration, in which cells inappropriately build scar-like collagen structures that disrupt normal tissue function. It is perhaps most significant in age-related diseases of the lung, heart, and kidney, but it is a general feature of old tissues. There are no effective and approved treatments capable of reversing fibrosis to any significant degree, but good evidence has arrived in recent years to suggest that senescent cells, one of the root causes of aging, are also an important contributing cause of the regenerative dysfunction that leads to fibrosis. Senolytic therapies capable of selectively removing senescent cells from an organ with fibrosis should prove helpful.

In that context, it is interesting to look over this recent demonstration of attenuated lung fibrosis via metformin treatment. Metformin is thought to modestly slow aging, being a form of calorie restriction mimetic, but as such treatments go, it is notably poor and unreliable. The animal data is highly varied when it comes to practical outcomes on aging and longevity. The beneficial effect on fibrosis observed here is thought to be mediated via mitochondrial function. Given what is known of metformin in aging, cellular senescence in fibrosis, and the role of mitochondria in programmed cell death, removing problem cells from tissue, it is tempting to speculate on the destruction of a fraction of the senescent cells in a fibrotic organ. But again, we know that metformin is unreliable in animal studies, while senolytics are exactly the opposite. So other mechanisms seem more likely, such as a change in cell behavior prompted by better function in mitochondria.

Pulmonary fibrosis can develop after lung injuries like infections, radiation, or chemotherapy, or it can have an unknown cause, as in idiopathic pulmonary fibrosis, or IPF. IPF is a progressive, and ultimately fatal, lung disorder. In experiments using lung tissues from patients with IPF, mouse lung fibroblasts, and a murine model of lung fibrosis, a team showed the reversal of lung fibrosis and the underlying cellular mechanisms affected via drug treatment. Interestingly, the drug that accelerated the resolution of lung fibrosis is metformin, which is a safe and widely used agent for non-insulin-dependent diabetes. The research focused on AMP-activated protein kinase (AMPK), an enzyme that senses energy state in the cell and regulates metabolism. Researchers found that AMPK activity was lower in myofibroblast cells within fibrotic regions of human lung tissue from IPF patients. Myofibroblasts deposit extracellular collagen fiber as part of the fibrosis process. These myofibroblasts were metabolically active and were resistant to the programmed cell death called apoptosis, a natural process that removes more than 50 billion damaged or aged cells in adults each day. Activation of AMPK in myofibroblasts from lungs of humans with IPF, using the drug metformin or another activator called AICAR, led to lower fibrotic activity. AMPK activation also enhanced the production of new mitochondria, the organelles in cells that produce energy, in the myofibroblasts, and it normalized the cells' sensitivity to apoptosis. Using a mouse model for lung fibrosis elicited by the anti-cancer drug bleomycin, the research team found metformin treatment, starting three weeks after lung injury and continuing for five weeks, accelerated the resolution of well-established fibrosis. Such resolution was not apparent in AMPK-knockout mice, showing that the effect of metformin was AMPK-dependent. "Together, our studies support the concept that AMPK may function as a critical metabolic switch in promoting resolution of established fibrosis by shifting the balance from anabolic to catabolic metabolism. Additionally, we provide proof-of-concept that activation of AMPK by metformin or other pharmacologic agents that activate these pro-resolution pathways may be a useful therapeutic strategy for progressive fibrotic disorders."

Link: http://www.uab.edu/news/research/item/9567-metformin-reverses-established-lung-fibrosis