Why Our Clients Don't use Metformin

Athletes without diabetes who are taking metformin are sabotaging their performance and possibly even their longevity and by the end of this video you will understand why and and what you can do instead.

VO2 max measures how efficiently your body uses oxygen during exercise. It’s a key indicator of cardiovascular fitness.  Studies have shown that metformin can reduce VO2 max improvements from exercise by up to 50% in older adults at risk of diabetes and by 40-60% in middle-aged pre-diabetics and diabetics. This means that your hard-earned gains in cardiovascular training could be significantly reduced while on metformin.

Metformin has many functions, but in the context of reducing VO2 max gains It is because metformin partially inhibits mitochondrial Complex I, which is one of 4 main complexes that make up the electron transport chain located on the inner mitochondrial membrane. 

Mitocomplex 1 drives ATP which is the energy currency of cells, and without enough of it you will die. The extreme destructive power of mito 1 inhibition can be witnessed when looking at the drug called rotenone, which causes severe cell cycle arrest, neurodegeneration, and its even been used to induce parkinsons disease by causing a significant loss of dopaminergic neurons.

Mitocomplex I inhibition also leads to an increase in lactic acid. Normally, during exercise, an acidic environment builds up in your muscles, which can reduce performance. Compounds designed to counteract this, such as the probiotic strain TWK10 and bicarbonates that mitigate acidosis, can improve performance. While lactic acidosis is rare with metformin and typically does not reach toxic levels, it still contributes to increased lactic acid, which is important to be aware of.

While a small reduction in Complex I activity with metformin doesn’t cause extreme harm, it does decrease the ATP:AMP ratio, which triggers the energy sensor AMP kinase. Additionally, two other upstream pathways of metformin also support AMP kinase activation: STK11 and ATM. Downstream from Complex I inhibition, there is an increase in glucose uptake into intestinal cells through enhanced GLUT1 function and glycolysis genes.

AMP K leads to various beneficial effects downstream including the upregulation of glucose transporter 4 which shuttles glucose from the blood into muscle cells, and activation of genes like FNDC5 which activates irisin. This is a major health promoter which actually upregulates mitocomplex 1, but its not enough to counteract the initial inhibition otherwise metformin wouldn't result in 50% reduced VO2 max gains from exercise. AMPK also activates FOXO3a, which is one of the most studied and proven genes for longevity and overall cellular repair. Many SNP’s exist for this gene which are associated with longevity. 

While AMPK activation has positive outcomes, inhibiting Complex I is a bad way to go about it because this reduces NAD+ production. NAD+ is essential for preventing polyploidy cells and tetraploid cells, which are cells that gain 1 or 2 additional sets of chromosomes. This contributes to endothelial dysfunction and cardiovascular disease by causing an overburden of oxidative stress that over time leads to a dysfunctional phenotype which causes cell death, inflammation, and a change of genes which cause extracellular matrix remodeling. Exercise naturally boosts NAD+ levels by enhancing Complex I activity. Since metformin inhibits Complex I, it diminishes some of the protective benefits of exercise. This means you’re not only achieving less improvement in VO2 max but also missing out on some key cardiovascular benefits from exercise.

You could just supplement with NAD + precursors like nicotinamide riboside, but this is still less beneficial than exercise according to 1 study. And since the number of polyploid cells in the human aorta reaches 30% the total number of endothelial cells by age 40, we really need to do everything we can to prevent this from worsening, which means no compromises.  

Now you may be asking yourself, why is metformin protective then? Its because high glucose levels also drive and accelerate this dysfunctional phenotype. This makes it net protective in diabetics, but if you don't have diabetes should you be using it? And even if you do, is it the best option?

According to me, Brenden Henry, anything which is not optimal to your goals shouldn't be used as the first choice. So I will cover alternatives to metformin in just a minute, but let's cover the other damaging effects of metformin first.

Metformin has been shown to reduce testosterone levels in humans rapidly in a 1 month-long trial, leading to a longer three-month study comparing it to a control group and confirming the findings. Testosterone levels are rapidly declining in younger populations; for instance, young men today average around 481 ng/dl, compared to 501 ng/dl for men aged 45-71 in the 1980s. To help with this, I created a Testosterone Maximization course. In this course, I detail how I went from having low testosterone in my early 20s to achieving over 1,000 ng/dl through a combination of lifestyle factors, nutrition, supplementation, and alternative approaches to common medications like metformin that can lower testosterone levels. The course offers insights into achieving the benefits intended by such drugs without their negative downsides.

You can find more information and access the course at unyieldingvigor.com/

Mitocomplex 1 inhibition has also been associated with increased cancer metastasis, and reduced NAD+ levels which occur from Complex I inhibition have been linked to worsened cancer outcomes. NAD+ cofactors, on the other hand, are known to reduce metastasis and improve survival rates. Despite these problems, metformin still has anti cancer-protective effects due to its promotion of STK11 and ATM pathways upstream. These genes inhibit tumorigenesis and its been found that SNPs in STK11 that reduce its function are associated with a higher cancer risk. Additionally ATM plays a role in promoting dna repair pathways and promotes oligodendrocytes to myelinate axons, which is neuroprotective especially in older age and enhances signal transmission between neurons.

So why don't I recommend metformin to my clients then? The drawbacks of metformin—such as Complex I inhibition, reduced NAD+, decreased VO2 max gains, and lowered testosterone levels is just a dealbreaker to me and so the question everyone should be asking is, can we get the same benefits that metformin is purported to offer without the negative effects? Well of course we can, and thats what I recommend we do.

In 1 pilot study berberine was shown to be as effective as metformin at lowering glucose levels due to its ability to activate AMPK without inhibiting mitcomplex 1. However, I dont like berberine either due to the fact it can cause dna damage and because it has a strong cholinergic effect, which not everyone can tolerate. It does this by inhibiting 2 of the enzymes that break down acetylcholine, including ACHE and BCHE. This can cause feelings of agitation or anxiety in people who don't respond well to cholinergics. 

So what do I believe is the best treatment? Well, Irisin is amazing and does activate AMPK downstream, stimulating GLUT-4 and enhancing glucose uptake, but it does much more. It upregulates mitochondrial Complex I, which enhances NAD+ and is anti cancer and reduces cardiovascular disease.I suspect that when excercise was found to be more beneficial at raising nad+ than cofactors, it was due to irisin. It increases SIRT1 which NAD+ works through and to help assist DNA repair pathways. IT stimulates autophagy, to clear out damaged cells that are beyond repair and it stimulates telomerase which lengthens our telomeres, the protective end caps on cells, allowing for more cell divisions. It enhances thermogenesis by the mitochondria upregulation and also shifts white fat which is low in mitchondria to brown fat which is mitochondrial dense. Irisin activates NRF2, a potent antioxidant pathway, and improves heart health by reducing myocardial hypertrophy, lowering blood pressure, lowering glucose, lowering CRP, and of course as stated earlier the NAD+, all of which creates a more favorable metabolic profile. Irisin promotes muscle growth, neuroprotection through BDNF, and oligodendrocyte function for axonal myelination via downstream ATM activation from AMPK and separately the ERK1/2 pathway. Additional compounds can be used for synergy as well, but it’s crucial when formulating a stack to get things right, because excess myelin, for example, can actually go to cell bodies, which is detrimental. You want just the right amount.

While metformin has some benefits through its indirect activation of Irisin, which occurs downstream from ampk activation as well, it doesn’t provide a strong enough effect to counterbalance the negative impacts of Complex I inhibition. Evidence of this is in the reduced VO2 max gains by 50%. So its much better to have direct irisin activation.

But Irisin injections are expensive and not everyone wants to inject. Therefore, focusing on compounds which can activate Irisin can be effective. Additionally PGC1α which activates FNDC5/Irisin downstream or PPARA/G can be beneficial and there are some amazing compounds that can do this and if you get my coaching at unyieldingvigor.com I can recommend the very best ones for your goals.

These compounds enhance mitochondrial biogenesis and glucose utilization, making them effective for diabetes management and exercise performance. the glitizar family of drugs which include dual activators of PPARA/G are very effective in diabetics for lowering glucose levels and for even lowering cholesterol levels and fatty acid utilization. Lastly, if you have diabetes there would be even additional bonus points if you choose a compound which activates GDF11, which support pancreatic b cells proliferation, which are the cells that produce insulin, and reduces inflammation. Its been shown to diminish M1 macrophage polarization and facilitate M2 macrophage polarization which is very protective in severe acute pancreatitis too.

So you may be wondering if there is any 1 compound that can do all of the above? And the answer is YES. There is A naturally occurring tripeptide with extensive human studies proving its safety called Pinealon. In comparison to metformin pinealon improves endurance and still has the same theoretical benefits of metformin without any of the detriments. I discuss Pinealon frequently on my channel and wish more researchers would include it in well conducted trials for different conditions such as diabetes as an alternative to metformin. I am confident it would do really well, I personally know someone with diabetes who has a constant glucose monitor and he got fantastic results in lowered glucose levels with pinealon. 

But if you have diabetes you should check out my peptide mastery course at peptides.unyieldingvigor.com because for something serious like diabetes you want the best possible stack and there are other peptides which can synergize really well with pinealon and have been proven effective in human trials for diabetes management, type 1 and type 2.

And if you want to maximize your athletic potential or health, you should also check out my peptide mastery course because I cover 66 peptides and how to use them to heal diseases, improve your health, reverse aging, enhance athletic performance and more. ITs the first and only course on the internet covering all 40 of the khavinson peptides and an additional 26 bringing the total to 66 peptides. It includes cheat sheets, quick reference pdfs and 3 months worth of free questions you can ask me about peptides and I will give you my best answer. Just go to peptides.unyieldingvigor.com

And if you would like to take things even further, you should know that I offer coaching with optional genetic analysis. With this, I can look at SNP’s that you have which are problematic or beneficial for certain outcomes such as brain, cardiovascular system, longevity, etc. and give you a detailed explanation of what each of your SNP’s mean for you, and use them to help formulate an even better coaching program for you. 

I work with all types of clients. Recently, I helped someone get off methadone without withdrawals, resolved GI issues that a doctor couldn't fix, and healed a person from long COVID-related heart damage, chronic fatigue, and fainting after doctors said nothing could be done. So, if you have a health problem or just want an optimized health or workout program—whether it's for strength training or endurance competitions like triathlons—I’ve worked with all these cases and can help you achieve more than you might think is possible.

Just go to unyieldingvigor.com/coaching and sign up.

This has been brenden henry the worlds leading expert on peptide science discussing why metformin is not the best choice for you if you are an athlete who cares about performance and

what alternatives could better help you reach your goals. Thank you for watching—please like, share, and subscribe!