Posted on Dec 30, 2021, 5 p.m.
We recently came across this anti-aging and longevity presentation from Lance Hitchings’s strategies for a radically longer and healthier life blog, discussing metformin and berberine that we thought was worth sharing, and hope that you found it as interesting as we did.
Metformin and Berberine.They've been used for alternative treatments for diabetes and now they're being used as alternative treatments by the anti-aging and longevity community. And they're pretty much the same, right? Well, they are very alike, except for one big difference, that could make all the difference between choosing between them.
I’m going to compare metformin to berberine and take a look at how well both perform against aging, their similarities, and the one really big difference between them. Both metformin and berberine have been around for a while now, and they’ve both been in use for a long time in treating diabetes. But their use as a longevity treatment is fairly new, and that’s what we’ll be examining.
Even though they may work a bit differently, they have a lot of things in common. In fact, in the aging community, berberine is considered to be an alternative to metformin. And that’s probably for the same reason that it’s considered to be an alternative in treating diabetes. Like I said, in one form or another, both metformin and berberine have been around for a long time.
Metformin is derived from a plant called the French Lilac, and this plant has been used as an herbal remedy for treating excessive urination caused by diabetes since the middle ages. Metformin, the drug, was first described in 1922 and it was approved by the FDA in 1994.
Berberine, on the other hand, has been used in Chinese medicine since 3000 BCE. It’s an alkaloid found in the roots and bark of several plants. Things like European Barberry, which is where it gets its name, but also from the Oregon Grape, Goldenseal, goldthread, Phellodendron, and tree turmeric. And I want to say right here that both of these molecules need a lot more research, particularly as it applies to longevity science.
There’s a fair amount for metformin, but there are two particular studies going on right now that I’ll be excited to see concluded and find out what the results are. The first is the Metformin in Longevity Study, or the MILES study. Now, as I understand it, this trial is already completed, but the results aren’t out yet. At least, I haven’t been able to find them.
The second is the Targeting Aging with Metformin trial, also known as the TAME trial. This trial hasn’t even launched yet, and it’s going to be looking at 3,000 individuals between the ages of 65 & 79. And it will take 6 years to complete. But berberine is a sadly underrepresented molecule. While there have been a few studies centered around its performance on diabetes, there aren’t nearly enough studies looking at how it performs when used as an intervention to defeat aging.
The same mechanism that makes both of these molecules so effective in treating diabetes is probably why there’s both effective at extending health and lifespans. Metformin controls blood sugar levels in two ways. First, by reducing the amount of glucose that’s dumped into the bloodstream. It does this by both blocking the absorption of carbs in the intestines and by decreasing gluconeogenesis in the liver, which is where the liver creates glucose. But it also lowers blood sugar levels by accelerating the uptake of glucose. Metformin increases both insulin sensitivity and the absorption of glucose into muscles. Metformin also activates an enzyme called AMPK, which blocks gluconeogenesis and increases insulin sensitivity, but it also activates autophagy, a process that recycles cellular components. It may also play a role in treating or preventing cancer.
Studies in 2015 and in 2018 suggest that people with diabetes who are taking metformin might have a lower risk of cancer and have a better survivability rate than healthy people who are not taking metformin. They also have a better overall prognosis for lung, pancreatic, and breast cancer. Metformin also reduces triglycerides, resulting in a lower risk for cardiovascular disease. It improves gut health by increasing bacteria that are good at producing short-chain fatty acids that can contribute to weight loss and inflammation suppression. And it appears to be good at extending health and lifespans. It inhibits the mTOR pathway and the Insulin-like Growth Factor 1 signaling pathway. Blocking both of these pathways has been indicated in promoting longevity. It can also restore youthful methylation. It may reduce the amount of damage that accumulates from chronic inflammation and oxidative stress. And a study by the Veteran’s Administration suggests that it may reduce the incidence of dementia.
In another study, called the TRIMM study, researchers tried to regenerate lost thymic tissue. They were able to accomplish that, but they also reset the epigenetic clocks of the study participants back by 2 years, on average. And they did this using metformin along with HGH and DHEA. Metformin also acts as a calorie restriction mimetic, or CR mimetic. It’s been known for a while now that calorie restriction can improve longevity and it does this through activation of AMPK and autophagy, and by suppressing the mTOR pathway. All these things that metformin does, so, it’s considered a CR mimetic.
Now, let’s compare these attributes of metformin to berberine. Berberine has long been used as an alternative to taking metformin because metformin can have some nasty side effects. Now, metformin can cause digestive upset, such as diarrhea and nausea, but berberine can have those same effects. But metformin can also cause lactic acidosis in people with kidney disease, which can be fatal. It can also inhibit the absorption of vitamin B1. And berberine has neither of these side effects. And apparently, berberine is just about as good as metformin in treating diabetes.
Both can reduce glucose levels and control blood sugar. Both increase glucose consumption by inhibiting complex 1 of the electron transport chain, part of a process known as mitochondrial respiration. Both are CR mimetics and both activate AMPK and suppress mTOR. Both reduce inflammation and both apparently reduce cell division, leading to less telomere attrition. But berberine works a bit differently than metformin. It’s known for reducing oxidative stress and it does this by activating AMPK AND an enzyme called P38. Activating them both can cause the activation of a cellular protein called Nfr2, which regulates the expression of antioxidant and stress response proteins.
Berberine can inhibit inflammation by limiting the activity of a couple of pro-inflammatory enzymes called I-Kappa B kinase and Rho GTPase. And finally, it can lower cholesterol. Now, because it’s so similar to metformin in its actions, it should theoretically be just as good as metformin with cancer. But there’s just no data to back this up, so, I guess only time will tell.
Now, there are some drawbacks to each.
First off, you need a prescription to take metformin. You can’t just buy it over-the-counter. Berberine, on the other hand, is a supplement, not a prescription and it’s available without a prescription, just like any other supplement.
Metformin has very good bioavailability and is absorbed by the body quite well. Berberine, on the other hand, is not. It has lousy bioavailability and is not absorbed well. Not only that but about 80% of what IS absorbed gets metabolized in the liver, where it doesn’t do any good. It just gets broken down.
And finally, the primary drawback of berberine, in my opinion, is that there just aren’t nearly enough studies on it. We just don’t know enough about berberine.
Now, I want to move on to a subject that might be a bit controversial. It’s pretty well-known that both exercise and metformin can benefit longevity, and most longevity interventions are additive, meaning that the effects of one can be added to the effects of another. Both exercise and metformin improve levels of fitness, blood sugar levels, and insulin sensitivity. They both also boost mitochondrial function. Both work the same pathways and have similar effects. So it makes sense to assume that taking metformin with your exercise regime would amplify the effects of both. But a study shows that that’s not the case. In fact, it looks like exercise and metformin cancel each other out. People who were doing both metformin and exercise had about half the gains in the fitness of the people had who were taking a placebo with their exercise. They had negligible improvement in insulin sensitivity. Finally, the people on the placebo had about a 25% rise in mitochondria respiration, while those on metformin saw little if any improvement.
Now, as I said, this study is controversial. It was done on a small group of elderly people who didn’t do any exercise previously, and it was done over a short period of time. Everyone took the same dose. And they took really high doses, around 2 grams a day. So the researchers caution that this study doesn’t necessarily mean that you shouldn’t take metformin if you’re exercising. However, there is some evidence that might show that taking berberine instead of metformin is better if you’re exercising.
Now, there’s this study, which was done on a group of sedentary, overweight, middle-aged men, and they found that those who were doing circuit training while taking berberine had larger improvement in triglycerides, total cholesterol, HDL and LDL cholesterol, and in C-reactive protein than the guys who were just exercising or just taking berberine.
And this study done on diabetic rats showed that taking berberine improved the effects of aerobic exercise as evidenced by higher levels of antioxidant enzymes in the animal’s pancreatic tissues.
Ok. For me, this is the thing that makes a big difference between taking metformin and berberine. I exercise a lot. I'm trying to stave off sarcopenia and osteoporosis. Both are signs of aging. I'm also trying to keep up my mobility and my stamina and endurance. If taking metformin might cancel out all the exercise I do, that's a big deal. If berberine doesn't cancel out my workouts, that is reason enough right there to take berberine instead of metformin. But if berberine actually enhances the effects of exercise, improving markers for aging like c reactive protein or boosting the effects of aerobic exercise, that kind of cinches it for me.
I looked, but I couldn't find any studies showing that taking berberine cancels out the effects of exercise like there is with metformin. But that metformin study is controversial, and there’s just not enough studies done on berberine… so, what do you think? Do you feel like we can trust any of these studies? Do you know of any studies beyond the ones I've been able to find? Do you come to similar conclusions or do you have another theory? Many questions still remain.
One thing is for sure. We really need a lot more research on both metformin and berberine.
Alright, let’s wrap this up by talking about dosing.
If you’re taking either metformin or berberine as a longevity drug… well, there’s not much research to help figure out how much you should take. The study on metformin and exercise took two grams a day. The TAME study used a dosage of 1.7 grams, the same as the MILES study is proposing. The TRIMM study used a half a gram a day. I’ve heard recommendations of anywhere between a half a gram and 2 grams a day, and that you should take metformin either once or twice a day. I’ve heard that you should take a similar dose of berberine, somewhere between a half a gram and one and a half grams a day. However, berberine has a pretty short half-life, meaning that the body clears it pretty quickly. So you should spread your dosage of berberine out by taking it 3 or 4 times a day. I’d like to reiterate here that I’m not a doctor, or a researcher, or a scientist, and you should not be taking my opinion as a recommendation. Please consult your physician before taking either metformin or berberine.
As with anything you read on the internet, this article should not be construed as medical advice; please talk to your doctor or primary care provider before making any changes to your wellness routine.
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Materials provided by:
Metformin & Exercise: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351883/
Effects of Berberine & Exercise on Humans: http://ijhs.shmu.ac.ir/index.php/ijhs/article/view/610
Effects of Berberine & Exercise on Rats: http://mr.crossref.org/iPage?doi=10.18502%2Fijdo.v11i4.2882