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  • Writer's pictureRyan Allen

A pharmaceutical agent to combat diabetes… and aging?

Recently, a development was made in the effort to specifically diagnose my “form” of diabetes. As I have explained in previous posts, my case does not appear to fit either of the two models we often consider to be the main routes of developing this condition. To briefly summarize, my test results appear to be inconsistent with type 1 diabetes as it looks like I am still able to produce insulin, and I also lack the self-reactive antibodies that are typically indicative of this disease. Meanwhile, throughout this process I have struggled to believe that I could be a type 2 diabetic given that I do not check any boxes for serious risk factors, and that I meticulously watch my diet, exercise, and overall habits.


For those interested, my doctor’s and my current thinking is that I may have something distinct and largely genetic called mature onset diabetes of the young (MODY). In this form of diabetes, the hyperglycemic phenotype (the state of having high blood sugar) is masked until young adulthood, when certain hormonal changes eventually induce it. Eleven specific genes have been identified and associated with MODY, with different mutations in these genes constituting a variety of different pathologies that lead to this outcome.


For example, one such form of MODY is a mutation in the gene for an enzyme called glucokinase, which plays a critical role in the glucose-sensing mechanisms of the pancreas. This is important because our pancreas secretes insulin in response to high concentrations of blood glucose, and lessens insulin secretion when blood glucose is low. In other words, pancreatic hormone secretion in a blood glucose-dependent manner helps to keep our blood sugar at a comfortable level. So, if the pancreas thinks we have a lot less glucose in our blood, it will act like it. It will secrete less insulin than it should normally, and as a result the person will have a higher “baseline” blood sugar. This situation seems consistent with what I’ve seen on my continuous glucose monitor (CGM), and my case in general seems to match the description of MODY much more clearly than classical type 1 or type 2 diabetes, which is why I’m looking forward to having genetic testing soon to possibly confirm this diagnosis.


Despite this new thinking, however, I have continued in the meantime with a common general method of treatment for any diabetic, which is to begin taking metformin. This drug is incredibly cheap, and is well established as a potent anti-diabetic agent. For those curious about the mechanism (and for those not, you can skip a couple paragraphs), there’s a lot of research still to be done on metformin’s various pathways. One known effect is its partial inhibition of complex I in the mitochondria, ever-so-carefully disrupting the electron transport chain (ETC). It may seem quite counterintuitive for most reading this who understand the significance of the ETC (and how we probably could not survive more than a few seconds without it) that this could somehow be beneficial and not detrimental. In fact, as Dr. Nir Barzilai—one of the world’s experts on metformin—cautiously puts it, this drug is almost like a much milder form of cyanide. While that may understandably sound frightening, it’s crucial to recall that in biology, everything is pretty much always on a spectrum, and therefore it’s about finding the right balance. Of course, flipping an “off” switch for the ETC would make life impossible, but hyperactivity can also be harmful.


Metabolically, this weak mitochondrial toxicity of metformin alters the activity of proteins AMP kinase (AMPK) and mTOR (mechanistic target of rapamycin). It increases activity of the former, basically an “energy-regulating” enzyme, and inhibits the latter, a major nutrient-sensing hub of the cell. Both of these observations lead some to hypothesize that metformin functions as if it were mimicking a fasted, or nutrient-deprived state, which would have corresponding positive effects on blood sugar. In addition, as I’ve alluded to in previous posts and will explore much more in-depth in my next post, fasting and molecular mechanisms associated with a fasted state are believed to possibly convey a longevity benefit.


The several, widely varying molecular impacts of metformin could lead one to infer that it probably does far more than just lower blood glucose concentrations, especially if it predominantly functions by this energy/nutrient deprivation path. Not only does that inference appear to be correct, but the implications of these other effects could be profound, as metformin has displayed anti-aging properties across numerous studies from reputable sources. While this clearly may seem hard to believe, the data are there to suggest metformin’s potential efficacy in extending lifespan. The turning point for Barzilai was seeing a study that showed diabetics on metformin living longer than non-diabetics not taking the drug, which I must say was truly astonishing for me as well. Something about this drug was so effective at enhancing longevity that it overcame the burden of a major, chronic metabolic disease that is known to decrease healthspan, which is quite the feat.


While many of the exact mechanisms by which metformin functions remain unclear, hints are starting to emerge that will go a long way to explaining not only the drug’s efficacy, but also perhaps several keys to unlocking our biological potential to slow aging. I can’t wait to see where further research takes this exciting field, and I’m also looking forward to documenting my own experience with this drug.



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