You can ignore this note if you have no interest in metformin. If you are interested in metformin this has been a month of dramatically contrasting opinions on metformin, and even criminal activity. There are five stories lines below. On this website we will be reaching out to experts on metformin to get their input.
First: This is an animal study, and a note below: https://www.biorxiv.org/content/10.1101/863357v1. To me this is the most important negative research on metformin to date, especially for older patients, but it is a worm study. If you read the article you will find it is very nuanced breaking out multiple situations. The only issue when translating it from worms to humans is that the dosage they gave to worms is very high compared to a dose a human with type 2 diabetes or someone using it for longevity would actually take. As it is a worm study “late life” is ill defined and difficult to translate for humans, and it could be 60 or possibly 80 years old. Nonetheless, it speaks to a theme we have been noticing in all aging therapies we are reviewing at Juvenescence. What time of day you take a medication, what your age is, and even your physical state on any given day all play a role in dosage and the benefit of these age modifying therapeutics. Then when you add in any other supplements or drugs you are taking and the inherent drug to drug interactions it becomes a very complicated scenario. It is then very difficult to make recommendations to people as to what to take, and there are individual differences as well. As this industry progresses it will be imperative that we have companion diagnostics for all these therapies to guide us to the appropriate regimen for any individual.
A quick synopsis: If the worm data translates to humans it would seem to indicate people should take metformin when they are young and stop as they get older. I have been recommending to young people that they wait until the TAME study at Einstein University is done to see the results based on this single study, but this worm study would indicate they should start now. As this is a single worm study, I would still not recommend immediate use by a young person as we need to do further studies. Furthermore, as you will read the negative metformin effects seem to be offset if you take rapamycin, but rapamycin currently has toxicity issues so this is not viable.
Second: For young people there is another complication. Researchers at Oklahoma Medical Research Foundation, Colorado State University and the University of Illinois in a small study earlier this year showed that if you take daily metformin it compromises your ability to build muscle: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351883/. So, this is the second time that we have a negative study for people who are biohacking by taking daily metformin. Just when you think you are understanding metformin the research scientists at Einstein University say that perhaps it does diminish your ability to build muscle or bulk up, yet they say that although you will not look like a bodybuilder your muscle with exercise still becomes stronger. Suffice it to say this still needs to be sorted out with more studies. Based on this Oklahoma Medical Research Foundation, Colorado State University and the University of Illinois study I personally changed my pattern of taking metformin. Now I take it with my meal, but after exercise. I am not sure this is a solution if you’re trying to exercise and build muscle.
Third: Then there is this positive article on metformin and its role in weight loss: https://scitechdaily.com/secret-behind-metformins-weight-loss-and-anti-aging-benefits-revealed/
Metformin does seem to make you lean. This may be based on the effect referenced in our second story line above, which says you won’t bulk up. So, if you are older and pre-diabetic, or overweight should you take metformin? If so, what dose, and when during the day?
Fourth: Then there is this contaminated pill, which is just blatant malfeasance “crazy”:
https://www.usnews.com/news/health-news/articles/2019-12-06/fda-testing-levels-of-carcinogen-in-diabetes-drug-metformin. So far I have not read that it is in Europe, but the US and Canada are investigating the contamination in multiple drugs including metformin. This seems to be due to a manufacturer or manufacturers who have been guilty of inadequate diligence in monitoring the quality of their products. There have been a number of media articles and shows that talk about this contaminant causing cancer in people on blood pressure medications. The toxic element is NDMA. It was first discovered in Singapore, where NDMA was found in 3 of 46 brands. Unfortunately, one is linked to a specific Chinese manufacturer that has a factory in the US. This company creates the raw materials used by pharmaceutical companies that manufacture the pills. Novartis was the first to notice it in the antihypertensive medications.
Fifth: Although this is not from this past month it has been written about extensively over the past year, and that is another negative quality of metformin specifically for men. As you will read in this article metformin causes an increase in sex hormone binding globulin (“SHBG”) that binds to testosterone and decreases free testosterone. This manifests as lower sex drive and erectile dysfunction: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296448/
I will qualify this commentary by pointing out that it may be dose dependent, as the study was done in type 2 diabetics who were not using it for longevity, and if someone is on metformin this is easily tested as free testosterone and SHBG are all easy blood test.
Summary:
The safest thing to do if you are on metformin and you are older (I apologize as I am not sure what is older) is discuss this with your doctor to decide whether to stop. At Juvenescence we are looking into a test that we can recommend to tell you if metformin is indeed messing up your ATP and cellular energy.
The reason we need to review all of these scientific studies and continue to analyse metformin is that in some very large studies (one with over a hundred thousands patients who were taking metformin) they saw an increase in healthy life span. I’ve always been curious about its role in decreasing cancer and one of the forms of Alzheimer’s disease. There was a study that came out this past summer where patients on five drugs (which included metformin) did not see slowing or halting of aging, but based on changes to their DNA which happen with aging they found that the combination of drugs actually reversed aging. We clearly need to find drugs that have metformin like qualities without the metformin side effects.
So what will I do while this is being sorted out? I’m less concerned about the Oklahoma Medical Research Foundation, Colorado State University and the University of Illinois study as I have not seen a decrease in strength in the last seven years while I have been on metformin. I have lost weight. The negative effects with age from the latest worm study is disconcerting, but it’s a worm study. Having been involved in drug development now for over a decade I know how often worm data does not translate to humans. So, I will either stop it outright or go to a lower dose (500 mg) after exercise, and I will take numerous drug holidays where I stop for a few weeks or months. For anyone reading this I would recommend that you consult your doctor.
Clearly, there’s going to be a lot more information coming out on metformin now that it is being used for longevity. Eventually we will learn the time of day you should take it, the dosage you should take, sort out any age-related issues and if there are drugs that we should take to offset any negative affects.
It would seem along with all the other breakthroughs we are seeing in therapies that modify aging that a modified metformin like product without the negative qualities could easily be part of the cocktail. Another focus for Juvenescence and our competitors in our quest to slow, halt or reverse aging.
