Metformin Shown to Attenuate Lung Fibrosis in Mice

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."



"senescent cells, one of the root causes of aging"
Can you point out to the clinical medical studies that CONCLUDE this phrase that you are keep repeating in your posts?

Posted by: Adrian Crisan at July 5th, 2018 9:12 AM

@Adrian Crisan: It is a simple argument of deduction based on what is known in the general literature. Senescent cells arise from normal operation of youthful metabolism. Some senescent cells linger indefinitely once created. Old tissue has more of them. They cause various age-related pathologies. Therefore they are a root cause of aging, as they have no prior cause. That removing them reliably extends life in mice and reverses numerous measures of aging and age-related disease is supporting evidence.

I suggest you look to reviews of cellular senescence as a phenomenon for supporting references to the above; the literature is extensive.

Posted by: Reason at July 5th, 2018 12:12 PM

Clinical evidence, is what we look for in 2018 NOT deduction from arguments.

Other deductions leads to different outcomes.
Please post the links to Clinical Studies that clearly states that.

Are you familiar with Clinical Studies?

There is a big difference between an "accelerator" of aging and "a root cause"

Again, post the clinical studies that conclude they are
a " root cause" of aging.

Looking forward to read the studies that you will post.

Posted by: AdrianCrisan at July 5th, 2018 1:53 PM

@AdrianCrisan: You are, possibly deliberately, not grasping the point of the exercise. Also impolite. That senescent cells are a root cause of aging is the straightforward outcome of what we know of the biology of senescence. They are created in the same way in youth and old age; they linger; they cause harm; old tissues have more of them. Removing them extends life and reverses measures of aging in animal models.

I suggest you familiarize yourself with the biology of senescence. There are many good papers on the topic.

How would you even begin to argue that they are not a root cause of aging? What mechanism or mechanisms are you proposing which would make senescent cell accumulation entirely secondary to it?

Posted by: Reason at July 5th, 2018 2:13 PM

This is not an exercise. You claim something, and I'm looking to read the Clinical Studies that clearly states what you keep saying. Please post the Clinical Studies with reference number, what you said are concluding what you imply in your posts.

Again, can you post them, so we can verify them at

I'm not looking for blogs/books/etc but for Clinical Studies that are peered reviewed.

Until there are Clinical Studies that can be replicated in humans, there is no evidence, but just your opinion.

This is what we call science.

Posted by: Adrian Crisan at July 5th, 2018 3:19 PM

Despite of many decades of metformin widespread usage we have very poor understanding why it works at all. It seems metformin actions reduce some mitochondria functions and that should have a detrimental effect on the health...

Posted by: Cuberat at July 5th, 2018 4:46 PM

@cuberat -
You are confused, like the individual that maintain this blog. if you READ the study you can find out the following:

"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."

= "production of new mitochondria" = nothing about reducing mitochondrial function = you are confused

So please post Clinical Trials w/reference number when you post your opinion. We are not after "theoretical" rejuvenation/reverse aging, but we are after Clinical Trials that can be replicated in humans.

Than you.

Posted by: Adrian Crisan at July 5th, 2018 6:34 PM

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