Life Extension, Health Extension, and Metformin
One of the most prescribed drugs in the world appears to also have some profound anti-aging properties. Here’s the science.
Round about 2008 to 2009, scientists were poring over the 10-year case histories of 8,000 type 2 diabetics when they noticed something downright weird. The diabetics who’d been using metformin, a blood-sugar-lowering drug, exhibited a baffling 54% lower incidence of all cancers compared to the general population.
Not only did the drug appear to have a cancer-preventative effect, but the metformin users who did develop cancer had much higher survival rates. The earlier they’d started using metformin, the better their prognoses.
The observations had an understandably seismic effect on the medical community, and they began to subject the drug to intense scrutiny, not just for its potential cancer-thwarting properties or its value as a drug to treat diabetes but for the possibility that it may have numerous clinical applications, including lifespan extension in general.
Some, with big hand-rubbing plans of being modern-day Methuselahs, began taking the drug immediately, while others continued to patiently wait for more research to come in.
Me? I’m with the hand-rubbers. While I have no illusions about immortality, I’m confident the drug can extend health span, i.e., the length of time we can stay mobile, strong, free of disease, and relatively sexy.
I now hector nearly everyone I know in my personal life to take the drug. Granted, there are some alleged downsides to the drug (which I’ll get to later), but I believe its positive attributes outweigh the potential negative ones.
What Exactly is Metformin?
Metformin was originally derived from a medicinal herb, the French lilac (Galega officinalis), and was first described in Culpepper’s Complete Herbal in 1653. It was recommended for treating worms, fever, pestilence, epilepsy, and other ailments. However, in 1772, John Hill, an early botanist and author of the 26-volume opus, “The Vegetable System,” suggested the plant be used to treat symptoms of diabetes. It wasn’t until 1957, though, that a French physician named Jean Sterne began using Galega officinalis’ active ingredient, metformin, to treat “sugar disease.”
The drug gained quick acceptance in Europe, but the sometimes overly cautious FDA didn’t approve its use on this side of the pond until 1995. It’s since become one of the most prescribed drugs in the world (there are a lot of diabetics) and, at about a penny or two per pill, one of the cheapest.
So Why Exactly Am I All Hot About Metformin?
There are now nine generally accepted “hallmarks” of aging, and research has found metformin to have the ability to modulate, to varying degrees, each of them:
1. LOSS OF PROTEOSTASIS
As proteins are formed, they need to “fold” properly (protein homeostasis, aka proteostasis). If improper folding occurs, it can result in diseases like cystic fibrosis, Huntington’s disease, Alzheimer’s, and several other diseases or conditions, many associated with aging. Metformin, however, maintains proteostasis through inhibition of this protein misfolding and enhancement of autophagy (the process by which cells break down and destroy old or damaged cells), thereby attenuating aging.
2. TELOMERE ATTRITION
Telomeres are the protective caps that cover the ends of the chromosome. Aging is associated with attrition and shortening of these protective caps, but metformin can reduce this telomere attrition, at least in the case of leukocytes (white blood cells) in patients with age-related diabetes.
3. GENOMIC INSTABILITY
As we age, we’re more prone to DNA damage, but much of this, at least in the young(er), is offset by a huge DNA repair system. This system, of course, falls into disrepair as we age. It’s thought, though, that metformin protects genomic stability by inhibiting oxidative stress and regulating certain protein kinases involved in causing unwanted mutations.
4. EPIGENETIC ALTERATIONS
Aging often leads to changes in the chemical structure of DNA that harm the daily function of cells, resulting in several age-related diseases. Metformin, however, regulates cellular transcription and post-transcriptional activity through several distinct epigenetic modification mechanisms. For instance, metformin prevents vascular smooth muscle cell dysfunction by regulating certain RNAs.
5. DYSREGULATED NUTRIENT SENSING
If aging cells can’t “sense” energy status and the availability of nutrients, they can’t facilitate growth hormone and other growth factor signaling pathways. Several studies show that metformin can shore up this dysregulated nutrient sensing, including IGF-1 and mTOR signaling pathways and upregulation of AMPK (the cellular “master switch”) and SIRT1 (a protein that renders cells stress-resistant) signaling pathways.
6. MITOCHONDRIAL DYSFUNCTION
As mitochondria age, they lose the ability to produce ATP, the energy currency of the cell. On a large scale, this of course leads to impaired cell metabolism and health, ultimately affecting the body’s health and functioning. Metformin, however, has been shown to upregulate mitochondrial biogenesis, thereby ensuring a steady stream of energy production.
7. CELLULAR SENESCENCE
This term refers to “an irreversible arrest of the cell cycle” (Chen, et al. 2022) that can be caused by irradiation, mitochondrial dysfunction, chemotherapeutic agents, and oxidative and genotoxic stress, among other things. In short, cells get old but don’t die off like they should, instead continuing to produce undesirable or harmful chemicals. Anyhow, this phenomenon is considered to be a main driver of aging and its associated diseases. Metformin, however, reduces senescence in some cells by activating AMPK and thus restoring autophagic “flux.”
8. ALTERED INTERCELLULAR COMMUNICATION
Healthy cells need to communicate with each other through endocrine, neural, or neuroendocrine signals, but aging messes this up. Sometimes cells signal too little, or in the case of inflammation, too much (e.g., increased cytokine levels). Metformin, for example, reduces inflammation and subsequently puts the kibosh on the over-production of cytokines.
9. STEM CELL EXHAUSTION
Stem cells are unspecialized cells that can give rise to various differentiated cells. In other words, they usually play a role in tissue repair and regeneration. But in the case of the aged, the number of active stem cells is often depleted or even exhausted. Enter metformin. The drug appears to delay stem cell aging and even rejuvenate their power of rejuvenation by increasing antioxidation, activating AMPK signaling, and inhibiting mTOR so that autophagy (the destruction of old, malfunctioning cells) can occur smoothly.
It’s no wonder that I, along with thousands of other biohackers and progressive clinicians, are so hot on metformin. Clearly, the drug has some astounding properties on the cellular level, but what impact does all this cellular stuff have on the body as a whole? Does metformin appear to have any beneficial impact on actual human diseases other than aging?
It sure seems like it does.
Metformin vs. Diseases
Metformin appears to have several clinical applications, particularly those that are age-related. Let’s address the most obvious one first, followed by lesser-known applications:
METFORMIN AND DIABETES MELLITUS
Metformin has been used to treat non-insulin-dependent diabetes for over 50 years. It’s been shown repeatedly to reduce fasted blood glucose and glycosylated hemoglobin (more commonly known as A1C) in a dose-related manner.
METFORMIN AND CARDIOVASCULAR DISEASE
Several trials have shown metformin to have a protective effect against cardiovascular disease. The drug seems to improve endothelial health, attenuate the formation of plaques, favorably change the composition of serum lipids, lower systolic blood pressure, and even decrease left-ventricular mass index (a predictor of future cardiac events which, incidentally, is often elevated in lifters).
METFORMIN AND CANCERS
Metformin increases survival in patients with pancreatic cancer. One study showed that the drug reduced risk of breast cancer in women with type 2 diabetes, possibly by reducing serum levels of estradiol. Metformin also reduces the risk of colorectal cancer, in addition to improving the survival rates of colorectal cancer patients.
Other cancers that seem to be vulnerable to metformin include those of the esophagus and lung. The drug appears to pester cancer by impeding tumor cell proliferation, blocking the tumor cell cycle progression, and preventing genomic instability by inducing apoptosis and impacting the energy metabolism of the cell.
METFORMIN AND SKELETAL DISEASES
Metformin, probably because of its anti-inflammatory powers, plays a role in the treatment of osteoarthritis (OA). Animal studies have found it to protect the cartilage in joints by activating the AMPK pathway, thus delaying OA.
METFORMIN AND NEURODEGENERATIVE DISEASES
Most, but not all, research suggests that metformin might help prevent Alzheimer’s disease and cognitive decline in general. It might also help in patients with Parkinson’s, but some of the studies have been contradictory.
METFORMIN AND OBESITY
While not nearly as effective as semaglutide, patients using metformin almost always show a significant loss of body fat. This is largely because of its role in the regulation of glucose metabolism.
There are other mechanisms involved, though. For one, metformin prevents obesity in mice by upregulating the metabolic activity of brown adipose tissue (BAT). Likewise, it seems to foster and regulate intestinal bacteria that affect body fat levels.
The drug has also been reported to improve fatty liver, reverse steatosis (fatty liver disease), and stabilize abnormal transaminase levels (which can be indicative of liver disease).
The Invariable Downside(s)
After reading all this good stuff about metformin, you’re probably feeling like I offered you free massages followed by light, affectionate noogies for life. In other words, there’s a part of you screaming, “What’s the catch?”
There are a couple of potential drawbacks to using metformin, but they’re not bad, or, rather, probably not bad.
The first one is potentially serious but probably inconsequential. That likely sounds confusing. Let me explain.
The reason why it took the FDA so long to approve metformin was because it has the potential to cause something called lactic acidosis, which you’ve probably experienced if you ever did a ton of reps on almost any exercise. Of course, exercise-induced lactic acidosis, aka “the burn,” is by no means serious and clears up within seconds.
However, it’s possible to develop fatal lactic acidosis. Serious lactic acidosis is characterized by nausea, abdominal pain, and tachycardia. The reported frequency in metformin users, though, is 0.06 cases per 1000 patient-years, and nearly all those affected had predisposing factors. Still, it’s something to be aware of.
The second potential downside is that metformin is thought to blunt muscle hypertrophy. It’s possible, given that metformin inhibits mTOR signaling acutely after a bout of exercise. Unfortunately, the only studies on this alleged effect of metformin were conducted on older adults. However, one crossover study found that the chronic effects of metformin on exercise adaptations were less apparent, i.e., the effects were less pronounced in people who used the drug regularly.
Metformin also reduces levels of free testosterone in obese men with type 2 diabetes on a hypocaloric diet. Whether it affects non-obese men in the same way isn’t clear.
All that being said, metformin increases the number and vitality of satellite cells, which play a big role in building new/bigger muscle. This increase in satellite cells is especially true when the drug is combined with an increased intake of the branched-chain amino acid, leucine. And regarding amino acids in general, metformin appears to help regulate their metabolism, along with that of proteins in general, which seems like a positive thing for muscle hypertrophy.
There’s also evidence that taking high doses or prolonged use can increase the incidence of vitamin B-12 deficiency, but this is probably easily addressed by taking a daily B-12 supplement.
OTHER POSSIBLE SIDE EFFECTS
Lastly, metformin, at least at first, can cause diarrhea, nausea, and loss of appetite. In fact, a significant percentage of people, probably close to 15%, just can’t tolerate it.
Personally, I’ve used the drug for years without ill effect, but these potential side effects might make you understandably wary. Also, its waist-slimming effects, for me at least, outweigh the potential of it blunting the hypertrophy response. Besides, a little extra bit of testosterone, either through supplementation or injection, negates that particular worry.
The Pharmacokinetics and Dosage
Metformin is a bit unusual in that it’s not metabolized by the liver. Instead, it’s eliminated entirely through the kidneys, where between 30 and 50% of the dose is excreted unchanged in the urine.
There’s also a bit of a paradox in its usage instructions. Diabetics are instructed to take it with their biggest meal(s), but food interferes with the absorption of the drug. This may be problematical as far as getting the most bang for your buck because only 50 to 60% of it is absorbed, even under ideal conditions.
Of course, the recommendation to take it with meals is meant to curb any potential negative gastrointestinal effects. Again, personally, it’s never caused me any problems at all, regardless of when I take it.
I take (for life/health extension and fat-fighting purposes) one 500-mg. tablet a half hour before eating, twice a day. I try to space them out evenly: one tablet every 12 hours. (The maximum recommended dosage is 2550 mg. a day, and that large a dosage should probably be restricted to type 2 diabetics).
Do Any Other Compounds Mimic the Effects of Metformin?
There’s another plant-based compound that appears to have some of the same powers as metformin. C3G (cyanidin 3-glucoside) is a naturally occurring anthocyanin (flavonoid) found in blueberries, blackberries, acai berries, and all kinds of other dark-colored fruits and vegetables.
C3G reduces blood sugar, just like metformin. It also appears to increase the activity of brown adipose tissue and increase mitochondrial health, much the same as metformin. However, there aren’t any studies that pit the two against each other, except for blood sugar reduction: several studies found that C3G compares favorably to pharmaceutical glucose-disposal agents, metformin included.
Both C3G and metformin appear to do these things by upregulating AMPK signaling pathways. C3G may also mimic some of metformin’s other abilities, but the research isn’t there (yet).
Cost-wise, metformin wins as it’s incredibly cheap. However, metformin is a prescription drug and you’ll need to find a progressive doctor to prescribe it, while C3G is an over-the-counter supplement (Indigo-3G®).
Don’t Let Your Meat Cook
A whole lot of people in the medical/scientific community are understandably excited about metformin. However, many are still undecided as to whether metformin actually extends lifespan and they’re waiting for the results of the TAME study to come in before they commit.
TAME is an acronym for Targeting Aging with Metformin Trial, and it’s a series of nationwide clinical trials currently being held at 14 leading institutions across the country. The trials will span 6 years and involve over 3,000 individuals between the ages of 65 and 79. The studies will hopefully decide whether metformin can delay progression of age-related chronic diseases like heart disease, cancer, and dementia.
I’m thrilled they’re doing this, but part of me worries that metformin needs to be introduced at much younger ages to give it time for all those life-extending attributes to kick in.
Case in point, metformin has one life-extending power that I rarely, if ever, see talked about in research papers, and it’s this: The very fact that it lowers blood sugar is life-extending all on its own, and I don’t need to see the results of any 6-year studies to prove it, thank you.
Let’s say your fasting blood sugar is 90 mg/dl. Your doctor would be thrilled because anything under 100 is considered good (you’re classified as pre-diabetic if your fasting blood glucose comes in between 100 and 125).
However, even at 90 mg/dl, you’re still producing, albeit slowly, what are known as advanced glycation end products (AGEs). You know how foods brown when exposed to high heat? That’s a result of what’s known as the Maillard reaction, which results in the formation of the aforementioned AGEs.
The same thing occurs in the body when blood sugar is consistently at a higher-than-desired level. Yes, having high blood sugar slowly “cooks” your body. Proteins cross-link, kind of like they do when you fry an egg. You can imagine what this process does to tendons, skin, blood vessels, hell, every tissue in your body. It’s all conveniently classified under the term “aging.”
Imagine what’s possible when blood sugar levels are kept low(er) through metformin or some other glucose-disposal agent. Blood vessels would remain supple and resist atherosclerosis. Tendons would retain the elasticity of youth, as would skin. More broadly, aging would be slowed.
So, I’ll patiently wait for the results of TAME, but in the meantime, I’ll continue to take metformin (AND cyanidin 3-glucoside), confident that they’re doing their life extension/health extension thing.
If you want to try to introduce metformin into your health/life extension protocol, just ask your doctor for a prescription the next time you see them. If they’re hip to its science, they’ll likely give it to you. If not, it may take some convincing; maybe print off one of the reference papers listed below.
If your insurance covers it, great. If not, no worries because the average cost for one hundred 500-mg. tablets (almost a two-month supply, at least when using my dosing recommendations) is between $13 and $22.
As far as obtaining cyanidin 3-glucoside, that’s easier. Just click here.
Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes, Diabetes Care. 2009 Sep;32(9):1620-5.
Chen, et al., Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms, Theranostics, 2022; 12(6).
Zhou, et al., Metformin Inhibits Advanced Glycation End Products-Induced Inflammatory Response in Murine Macrophages Partly Through AMPK Activation and RAGE/ NFkB Pathway Suppression, J. Diabetes Res., 2016, Sep 28.
Luo, et al., Metformin in patients with and without diabetes: a paradigm shift in cardiovascular disease management, Cardiovascular Diabetology, 27 April 2019.
Morales, D., and Morris, A., Metformin Cancer Treatment and Prevention, Annual. Review of Medicine, vol, 66:17-29, 2015.
Petrocelli, et al., Metformin and leucine increase satellite cells and collagen remodeling during disuse and recovery in aged muscle, FASEB, 20 August, 2021.
Grace MH et al. Hypoglycemic activity of a novel anthocyanin-rich formulation from lowbush blueberry, Vaccinium angustifolium Aiton. Phytomedicine. 2009 May;16(5):406-15.
You Y et al. Cyanidin 3-glucoside attenuates high-fat and high-fructose diet-induced obesity by promoting the thermogenic capacity of brown adipose tissue. Journal of Functional Foods. 2018 Feb;41;62-71.