This article (just like any other on Grantigen) was not written by A.I. It doesn’t start with a vague general statement, then talk about the obvious, and then, maybe only in the third paragraph, you may begin to see something that was the reason for you to open this page. Pay attention to the pattern next time you read something of interest.
In order not to waste paragraphs and readers’ time, let us answer the question: If you have type 2 diabetes, metformin will indeed increase your lifespan because it treats the condition that shortens it. If you are healthy, and especially if you workout, metformin will not increase your lifespan. It is not a miracle drug because it was proven that diet and exercise have stronger positive effects on health. The beneficial effects do not add up. In fact, metformin makes exercise less effective (1) . There, you don’t need to read more. We just summarized the studies addressing this question for you. The exact pathways are not really important if you are not interested in the molecular mechanisms of our bodies.
However, new data always comes up, and who knows what the future holds? Maybe metformin in combination with, say, cinnamon will improve the already improved bodies through diet and exercise? This is the beauty of not knowing everything. One just needs to be open to new ideas and not heavily invested in the current state of things, as that always makes one reluctant to accept anything new.
Here is a more detailed explanation:
The second section of the article is for those who want a leisurely read with enough scientific information along the way.
Metformin was first synthesized in 1922 because there was some previous knowledge that the “toxic weed” Galega officinalis may help with diabetes (2). Diabetes was not understood in the ye olde times, but people did know that some disease that causes sweet urine existed. How did one find out whether one fellow’s urine was sweet? How did people find out that a particular plant among so many others could help with this particular condition?
It took some time before metformin was approved and prescribed for type 2 diabetes. It has been 70 years since then. The drug is considered safe and effective, but the interesting thing is that the exact mechanism of action is not fully understood. There have been many articles that are trying to pinpoint the exact mechanism, though it is known which cellular pathways it affects (3).
This would be a good time to say that metformin is off-patent now and also very cheap. There are efforts to create something new, patented, and way more expensive that will do the same job with possibly more side effects. The side effects can be easily mitigated with an appropriate advertising campaign. Humans are so predictable…
Our understanding of biological processes on the molecular level keeps growing. With that, the number of possible signaling pathways that need to be investigated also grows. Researchers have tried to figure out the role of metformin in the AMP-activated protein kinase (AMPK) signaling pathway, mTor pathway, IGF1 pathway, GLP1 pathway, DAF16 pathway, CBP pathway, and the role it may play in inhibiting mitochondrial complex I.
We can briefly summarize the findings here, but readers can find out more from (4).
1. The AMPK pathway is named after the 5′ adenosine monophosphate-activated protein kinase. As the name suggests, it is a kinase activated by adenosine monophosphate. Its function is to serve as a molecular energy sensor in cells. AMPK senses energy by comparing the ratio of adenosine monophosphate (AMP) to adenosine triphosphate (ATP). When the AMP/ATP ratio increases, it sets in motion processes of ATP production and glucose uptake. AMPK also regulates lipid metabolism processes. Metformin activates AMPK, which has positive effects on cell function, but as we mentioned before, so does exercise. (5)
2. The mammalian target of rapamycin (mTOR) plays an important role in proliferation and immune cell differentiation. It is activated in tumors. Metformin inhibits this pathway through the AMPK pathway, resulting in a lesser incidence of cancer, as diabetes is a risk factor for cancer (6).
3. Insulin-like growth factors (IGFs) affect cell proliferation, differentiation, and survival. Although this signaling pathway is considered “weak” by itself (7) and primarily augments other pathways’ signals, it too is affected by metformin (negatively), thus mimicking the calorie restriction situation that has been proven to increase lifespan. What would be the alternative to taking metformin in this particular case? Eating less, perhaps?
4. Glucagon-like peptide 1 (GLP1) has a role in the regulation of glucose levels by insulin secretion. Metformin enhances the release of GLP1, thus reducing glucose levels. (8).
5. DAF16 is specific for C. elegans, as many longevity experiments have been done on this nematode. The gene is involved in glucose and lipid metabolism. Metformin increases insulin sensitivity, which simulates a reduced calorie intake. Too much sugar in the diet leads to insulin insensitivity, and vice versa. C. elegans has a very different gut lining than humans, making drug uptake less efficient. For that reason, metformin concentrations in experiments with C. elegans are up to a thousand times higher than in humans. There is an up to 36% increase in lifespan in the worm that was attributed to the positive effect methformin has on its gut flora, i.e., killing the worm’s bacteria. The antibiotic trimetoprim had the same effect on the worms (3). Should we all take Bactrim to increase our lifespan?
6. AMPK-atypical protein kinase C (aPKC)-CREB-binding protein (CBP) has neuroprotective properties and a role in cell proliferation, growth, and apoptosis. CREB-binding protein (CBP), as its name suggests, binds CREB (a transcriptional factor), making it active. Metformin and insulin cause the dissociation of CBP from the promoter region, which results in halted expression of the downstream genes responsible for gluconeogenesis. In other words, metformin stops the synthesis of glucose through this pathway (9).
7. Mitochondrial complex I is the first complex in the respiratory chain of mitochondria. When metformin inhibits complex I, it leads to a higher AMP/ATP ratio (see above) and activates the AMPK pathway (4). However, these results were obtained in cell cultures. When tested in mice, mitochondrial activity was elevated. There is some kind of interaction between metformin and complex I, but it would be strange to learn that decreasing respiration leads to a positive outcome for the cell. It is well known that young cells have a higher respiration rate than old ones (10).
Metformin is a great example of how something from nature was translated into an effective drug. The only other class of drugs that come to mind are antibiotics. With so many articles written about this drug, it is normal to have high expectations, but doesn’t it already treat the condition for which it was intended? People just want more…
Science is close, but not always in a clear-cut scenario. We are constantly in the process of finding out new information. There have been examples when a solid scientific truth was shaken by new data and then eventually destroyed. This happens very slowly because of the opposition, which has vested interests, of course. The landscape of the world where useful information lives is cluttered with opposing statements and interests that constantly create noise. It takes a sharp mind with enough scientific background to cut through the noise and get to the truth. Some people are lucky to be born with a natural sense for that thing, usually called common sense. Others must go through the process of practicing the skill. The third group never masters it. Not to deviate too much from the topic of the post, we should say that metformin is a great drug that unfortunately doesn’t fulfill the hopes of extending life. Not changing one’s lifestyle and only relying on a single molecule to live longer is tempting for many people. Metformin’s role in cancer prevention has not been researched as thoroughly. Maybe it possesses some serious anti-cancer properties that we are not yet aware of?
References:
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2. Bailey CJ, Day C. Metformin: its botanical background. Pract Diab Int. 2004 Apr 21;3
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