Metformin Anti-Aging Therapy: Latest Research on the Longevity Benefits of Taking Metformin

When I tell anyone that I am researching longevity, one of the first questions I get asked is, “Does metformin really slow down aging?”

Quick answer? We don’t know for sure. Yet. But we think it does. And here’s why.

Ten years ago, metformin was a bit of a hidden pearl for the longevity geeks like me—in that its longevity-boosting properties hadn’t yet been discovered by many, and Nir Barzilai was pretty much the only high-profile scientist really trying to push it into the mainstream.

Now, of course, everyone is talking about metformin and its presumed effects on lifespan.

So what I want to do today is explore the many aspects of how metformin came under the spotlight, why it’s such an interesting molecule, how it works to combat Type 2 Diabetes, and how it works to produce lifespan extension in so many organisms (not just humans).

Metformin is the most prescribed oral antidiabetic drug used since 1957, best known as first-line treatment for Type 2 Diabetes.

Structurally, metformin is a biguanide with blood glucose-lowering properties that, unlike insulin secretagogues or insulin therapy, do not involve raising insulin levels in the body.

Historically, metformin is not the first biguanide to be used against high blood sugar. Goat’s rue (aka Galega officinalis or French Lilac), a plant used in traditional European herbal medicine as a diuretic, was found to be rich in galegine, a derivative of guanidine with blood glucose-lowering activity.

Metformin’s “close cousins”, phenformin and buformin, were early biguanides used to treat Type 2 Diabetes but were eventually withdrawn in the early 1970s due to higher lipophilic profiles that caused lactic acidosis and heart disturbances, leading to death in some cases.

Unlike phenformin and buformin, however, metformin hydrochloride (the pharmaceutical formulation metformin is available as) is unusually hydrophilic for a drug, which makes passive diffusion through cell membranes unlikely and requires active transport via the plasma membrane monoamine transporter (PMAT)—a protein encoded by the SLC29A4 gene.

Metformin’s reputation suffered for years due to its association with the two withdrawn biguanides, but after continuous scrutiny, it was eventually introduced to the US in 1995.

Its use, however, really took off in 1998, after the UK Prospective Diabetes Study (UKPDS) showed long-term cardiovascular benefits of using metformin in overweight individuals with type 2 diabetes.

While metformin is best known for its effects in treating type 2 diabetes, there are many observed health benefits when taking this drug for other indications, including prediabetes , gestational diabetes , polycystic ovarian syndrome (PCOS) , obesity , and potentially even non-alcoholic fatty liver disease (NAFLD) .

But perhaps one of its most promising effects may be improving healthspan and increasing lifespan.

Nir Barzilai, the director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York, was among the first to draw attention to the longevity-promoting effects of metformin.

In 2015, he met with the FDA to discuss the now well-known TAME (Targeting Aging with Metformin) trial. FDA is an agency tasked with regulating medications that treat known indications/diseases. For this reason, Barzilai and his team chose the name of the trial with intent—namely, aiming to indicate that “aging” is a disease that should be prevented or treated, just like any other disease.

And for the first time, in 2018 the World Health Organization (WHO) added a new code in its latest version of the International Classification of Diseases (ICD-11), “Code MG2A: Old age”.

However, it’s important to note that most of the positive effects of metformin have been shown in individuals with metabolic dysfunction. Yet nowadays, more and more metabolically healthy people are taking the drug in the hopes of prolonging their lifespan.

This is why it’s worth reviewing the data we have so far on metformin’s health effects, and whether there are any adverse effects in healthy individuals.

We cannot discuss the health benefits of metformin without first explaining its main use, which is to lower blood sugar.

Metformin exerts its blood sugar-lowering mechanism on the liver to lower glucose production, and on the gut to increase glucose usage.

Molecularly, metformin inhibits the mitochondrial electron transport chain (ETC) in the liver, leading to an increase in AMP-activated protein kinase (AMPK), increased insulin sensitivity, and decreased cyclic AMP (cAMP), which ultimately reduces gluconeogenesis.

Additionally, independent of AMPK, metformin also acts on the liver to inhibit fructose-1,6-bisphosphatase via AMP.

These mechanisms combined result in a glucose-lowering effect of as much as 3.9 mmol/L (70 mg/dL).

It’s important to stress that metformin lowers blood glucose without increasing insulin production. In other words, metformin is not an insulin secretagogue, unlike sulfonylureas and meglitinides.

This becomes a vital point when considering the negative impact of insulin resistance.

Insulin resistance is the dysregulated metabolic state that forms the basis of metabolic syndrome—a disorder found in most chronic diseases, including obesity, type 2 diabetes, cardiovascular disease, cancer, Alzheimer’s disease, non-alcoholic fatty liver disease, and polycystic ovarian syndrome.

It’s been known for many years that a continuous state of hyperinsulinemia (high insulin in the blood) can lead to insulin resistance.

For these reasons, taking anti-diabetic drugs that increase insulin production is, in fact, the opposite of a desirable therapeutic strategy.

In contrast, metformin has been shown to be an insulin-sensitizing drug, which may be another mechanism through which it is acting to lower blood sugar.

As mentioned above, metformin is known to mildly inhibit the mitochondrial respiratory chain, but not to the extent of inducing actual dysfunction.

More specifically, metformin has been shown to inhibit the mitochondrial complex I, an enzyme also called NADH dehydrogenase, which oxidizes NADH molecules generated through the Krebs cycle and uses the two gained electrons to reduce ubiquinone to ubiquinol (CoQ10).

This effect—where a compound or behavior “stresses” the mitochondria without producing actual lasting damage—is called “mitohormesis”.

Similar to the principle of “whatever doesn’t kill you, makes you stronger”, mitohormesis seems to show that whatever doesn’t kill your mitochondria, makes you healthier.”

The presumed mechanism by which metformin induces mitohormesis is the reallocation of the electron flux towards the production of Reactive Oxygen Species (ROS) in complex I. In other words, metformin causes the production of ROS to such a degree that it slightly “stresses” the mitochondria—enough to stimulate an increase in energy production, but does not cause lasting damage.

AMPK, an enzyme mentioned above, is a master regulator of cellular energy homeostasis. In a nutshell, when energy levels are low within a cell, AMPK senses that and promptly switches off anabolic pathways (these are pathways that induce growth but consume energy), while simultaneously turning on catabolic pathways to produce ATP, the universal cellular energy currency.

What AMPK actually senses is a change in AMP:ATP and ADP:ATP ratios. Because metformin inhibits complex I in the mitochondria, less energy is produced in the cell, leading to higher AMP:ATP and ADP:ATP ratios, which in turn activates AMPK.

AMPK is widely regarded as one of the four main longevity-promoting pathways. The other three are mTOR (mechanistic target of rapamycin), IIS (insulin/IGF-1 signaling pathway), and the sirtuin pathway.

Interestingly, metformin’s activation of AMPK has been shown to decrease advanced glycosylation end product (AGE) formation in human neural stem cells (hNSCs).

It has been known for many years that metformin inhibits mTOR, though our understanding of the exact mechanism through which that happens has evolved over time.

Due to its main action of activating the AMPK pathway, it was thought for a long time that metformin must be inhibiting mTOR as well, since AMPK is a known mTOR inhibitor. This expectation was confirmed by several studies (Study 1, Study 2).

But interestingly, it was found that, while metformin does inhibit mTOR, it does so in an AMPK-independent manner, depending, instead, on the activity of Rag GTPases.

Another study showed that metformin also inhibits mTOR signaling by down-regulating specificity protein (Sp) transcription factors, which in turn decreases expression of the insulin-like growth factor-1 receptor (IGF-1R) resulting in mTOR inhibition.

This interesting, multi-pathway manner in which metformin affects mTOR activity could certainly be an explanation for the observations that metformin positively affects lifespan and healthspan.

It is largely recognized that mTOR is one of the primary inhibitors of autophagy, so any agent or behavior that decreases its activity, theoretically, increases autophagy.

But what is autophagy? In a very simplistic way of looking at it, if the body goes without food for extended periods of time, it begins to consume itself. The origin of the word “autophagy” is Greek and it quite literally means self-eating—”auto”: self, “phageîn”: to eat).

Normally, if we are in a constant “fed” state and never go without food for more than 10-12 hours (which is when we sleep), autophagy rarely occurs, so our cells don’t get the chance to recycle old components and get rid of those that are a surplus. This also means that we begin to accumulate wasteful bits that, over time, may cause issues.

And while fasting is the easiest way to activate autophagy, metformin also has the same effect by simultaneously activating AMPK and inhibiting mTOR. This is considered to be one of the main mechanisms through which metformin confers antitumorigenic (anti-tumor formation) properties.

It is only because of Type 2 Diabetes that metformin was first produced, so its effects on lowering blood sugar are, overall, the most extensively studied.

While the mechanism for blood sugar-lowering was detailed above, it’s worth repeating that—as a first-line therapy—metformin has treated more people than most other drugs in history, protecting both the micro- and the macrovasculature in the process.

Section 9.4a of the “Standards of Medical Care in Diabetes—2022” published by the American Diabetes Association (ADA) states:

First-line therapy depends on comorbidities, patient-centered treatment factors, and management needs and generally includes metformin and comprehensive lifestyle modification.

The UKPDS revealed the efficacy and safety of metformin use in individuals with T2D, as well as highlighted that subjects who were overweight and taking metformin had lower rates of myocardial infarction and mortality than controls—an outcome that put metformin on the map of potential “longevity drugs.”

For many years, observational studies have shown a decreased occurrence of cancer in individuals taking metformin. One study, in particular, showed a 23% reduction (statistically significant) in the incidence of any cancer in patients on metformin, which sparked the hypothesis that metformin use might lead to a decrease in cancer risk in patients with type 2 diabetes.

For example, a meta-analysis of 11 studies on 181 patients with locally advanced or metastatic pancreatic cancer that could not be treated with resection showed a significant improvement in survival in the metformin-treated group compared with controls. Additionally, metformin also improved survival in patients with resection or with locally advanced tumors—but not in patients with metastatic tumors. This suggests that, if given in early stages of pancreatic cancer, metformin can be a powerful tool in this incredibly deadly disease.

T2D is known to increase the risk of several types of cancer, such as colon, pancreas, rectum, and liver cancers, compared to non-diabetic patients, so it might sound logical that just by controlling blood sugar levels one might see an advantage in terms of cancer risk.

But is the mechanism by which metformin is implicated in cancers related to its ability to control T2D or some other property?

Mechanistic studies have indicated that, while metformin can indeed indirectly affect cancer cell growth and proliferation by lowering blood glucose and insulin via the PI3K/AKT/FOXO1 pathway, it also has direct effects on cancer cells via AMPK activation and complex I inhibition, as suggested in the graphic below:

One recent study, however, appears to contradict the previous findings by showing that:

Metformin forces [cancer] cells to rewire their metabolic grid in a manner that depends on AMPK, with AMPK-competent cells upregulating glycolysis and AMPK-deficient cell resorting to ketogenesis.

It is also important to note that not all studies investigating metformin’s efficacy in preventing or combatting cancer have had promising results.

Most notably, a randomized controlled trial investigating whether patients with metastatic breast cancer could benefit from adding metformin to standard chemotherapy, and a meta-analysis of RCTs on the addition of metformin to anticancer therapies in advanced/metastatic cancers showed no significant benefits with metformin use.

These findings seem to suggest that, while metformin may be great for prevention in cancer cell proliferation in people with T2D, it may not be of use in advanced cancer stages.

Metformin is not only known to enhance insulin sensitivity at the cellular level but also appears to have direct effects within the ovary.

This has made it an obvious target for investigations into its effects on PCOS.

In combination with lifestyle changes, metformin is recommended by an international evidence-based guideline for PCOS management for the management of weight, hormonal and metabolic outcomes. Additionally, studies also show benefits of metformin use for hirsutism and acne associated with PCOS.

The literature has shown that metformin may have multiple positive effects in PCOS, as this article documents:

Metformin is an effective ovulation induction agent for non-obese women with PCOS and offers some advantages over other first line treatments for anovulatory infertility such as clomiphene. For clomiphene-resistant women, metformin alone or in combination with clomiphene is an effective next step. Women with PCOS undergoing in vitro fertilisation should be offered metformin to reduce their risk of ovarian hyperstimulation syndrome.

It is interesting to note that a variety of clinics around the world use metformin off-label in the treatment of PCOS for various target outcomes. For instance, The Advanced Fertility Center of Chicago offers fertility treatments with metformin for women with PCOS.

Over the years during which metformin has been first-line therapy, large cohort studies have shown weight loss benefits associated with its use.

A recent systematic review of 24 RCTs investigating the efficacy and safety of metformin for obesity found that metformin has modest but beneficial effects on weight and insulin resistance, as well as a tolerable safety profile in children and adolescents with obesity. The review showed modest decreases in BMI, BMI z score, and homeostatic model assessment of insulin resistance (HOMA-IR).

However, another recent systematic review and meta-analysis of 38 studies investigated whether metformin reduces obesity in children and adolescents. Their findings indicated a significant reduction in BMI, body weight, waist circumference, and fat mass, but no change in lean body mass.

A long-term randomized double-blind clinical trial of metformin with a follow-up after 7-8 years showed that weight loss was significantly greater in the metformin group than in the placebo group at follow-up (2.0 vs. 0.2%, P < 0.001), correlating with the degree of metformin adherence (P < 0.001). In other words, the more compliant the patients were with taking metformin, the more likely they were to lose weight and keep it off.

While metformin should in no way be considered a “weight loss pill”, it’s important to note it may be of use in people with obesity, and might also be an adjuvant in weight loss regimens.

It’s useful to start this topic by mentioning that, until recently, most evidence pointed towards the fact that metformin is not useful in treating Non-Alcoholic Fatty Liver Disease (NAFLD) or preventing its progression to non-alcoholic steatohepatitis (NASH), as shown in the following quote from the American Academy of Family Physicians (2019):

Metformin does not seem to be an effective treatment for nonalcoholic steatohepatitis. There are no studies evaluating whether metformin improves long-term patient-oriented outcomes such as progression from NAFLD to nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, or death from liver failure.

Yet more recent studies seem to indicate that metformin attenuates the onset of NAFLD , partly due to its positive effects on intestinal microbiome composition and barrier function. One study, in particular, shows metformin reduces hepatic steatosis in mice by promoting autophagy.

More research is needed in determining whether metformin is a candidate for NAFLD therapies, but it is clear that there are increasingly promising signs it can play a role in fighting the increasing “silent” NAFLD epidemic.

Metformin’s contribution to improving cardiac arrhythmias is less known compared to its effects on metabolic syndrome diseases. Yet the findings on metformin & arrhythmias can be summed up with a quote from this study:

Patients on metformin monotherapy had significantly reduced risk of atrial arrhythmias, ventricular arrhythmias, and bradycardia compared with monotherapy with sulfonylureas

Metformin’s action on small conductance calcium-activated potassium channels (SK channels) showed a significant reduction in cardiac fibrosis and attenuation of arrhythmia in diabetic Goto-Kakizaki (GK) rats, as well as reversal of diabetes-induced alterations in atrial SK channel expression.

The importance of ion channels is beginning to be revealed by the emerging field of bioelectricity, and the positive effects of metformin on longevity may just be mediated via its interactions at the bioelectrical level.

While the indication for cardiac arrhythmias is currently off-label, it is positive future studies may support treatment of cardiac arrhythmias with metformin.

Animal studies have shown mixed results when it comes to metformin’s ability to increase lifespan.

Studies in C. elegans nematodes (roundworms) have shown that metformin extends median lifespan in a dose-dependent manner and improves healthspan.

In contrast, a study in fruit flies (Drosophila melanogaster) showed that metformin did not increase lifespan in male or female fruit flies and that in high doses it caused toxicity.

A study showed that the chronic treatment of female transgenic HER-2/neu mice with metformin prolonged their average lifespan by 8% (p < 0.05) and the maximum lifespan by 1 month compared to control mice. More youthful phenotypes were also observed in the Metformin group, with prolonged estrous function and decreased blood glucose and triglycerides.

Another study looking at female SHR mice also showed increased lifespan and tumor postponing—if the metformin treatment is started early in life.

More notably, a study by Rafa de Cabo and David Sinclair’s group showed that long-term treatment of male mice (C57BL/6 and B6C3F1) with metformin (0.1% weight for weight) starting at middle age prolonged their lifespan  Conversely, the study showed that a higher dose (1% w/w) was toxic.

The metformin-mice showed greater energy metabolism (analyzed by indirect calorimetry) with an increase in fatty acid β-oxidation, while de novo lipogenesis (DNL—new fat making) was decreased, especially in the liver.

Again, this study also showed that the healthspan of the mice was improved as well, with rotarod, treadmill and open-field tests indicating the metformin-fed mice had better fitness. A notable observation was the reduction in lens opacity in the C57BL/6 mice, which are prone to cataracts. The study also shows numerous other benefits, including inflammatory profile, insulin sensitivity and improved overall metabolic flexibility.

Interestingly, a study on Fischer-344 rats showed no significant improvement in lifespan by metformin treatment.

And perhaps the most notable set of studies on metformin in animal models is the Intervention Testing Program (ITP) cohort by Richard Miller and Randy Strong’s group. Their findings showed that at a dose of 0.1% in the diet, metformin alone does not significantly increase lifespan—however, combined with rapamycin:

“[Metformin] robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone”

As mentioned above, over the years observational studies have shown that people taking metformin are generally in better health than individuals who do not take it.

Your Content Goes HereIn recent years, however, clinical trials have attempted to test whether these observations indicate a causal relationship or whether it is merely a correlation.

The MILES clinical trial (Metformin in Longevity Study) showed that metformin modified several pathways associated with aging, including metabolic pathways, adipose tissue and fatty acid metabolism, mitochondria, collagen trimerization and extracellular matrix (ECM) remodeling, and the MutS genes, MSH2 and MSH3, which play a role in DNA mismatch repair.

But perhaps one of the most exciting studies on metformin is Nir Barzilai’s TAME clinical trial, which is in fact a series of trials conducted at 14 leading research institutions with over 3,000 participants between the ages of 65-79.

TAME aims to test whether individuals taking metformin can delay the development or progression of age-related chronic diseases, such as heart disease, cancer, type 2 diabetes, and dementia. Due to the safety profile of metformin and the number of studies indicating its longevity-promoting effects, TAME will attempt to settle whether metformin can delay the aging process as a whole.

Exercise is one of the most potent drugs we have in our proverbial longevity toolkit. Given the number of pathways it modulates, it would come as no surprise that, when combined, metformin and exercise may affect some of the same pathways and therefore potentially cause harm rather than a hormetic effect.

Recent studies have supported this hypothesis, and high-profile scientists such as Dr. David Sinclair have cautioned against taking metformin while doing vigorous exercise.

Most notably, a double-blind placebo-controlled trial involving 27 healthy older adults (62 ± 1 years) found that taking metformin inhibited mitochondrial adaptation and improvements in cardiorespiratory fitness, as well as attenuating the increase in whole-body insulin sensitivity and VO2 max after aerobic exercise training (AET).

Petter Attia, MD offered a very nuanced interpretation of the study which seemed to suggest that there may be no straight answer on whether metformin is contra-indicated with exercise and that the dosing, timing, and scheduling of metformin might be crucial in ensuring its efficacy.

Given the vast amounts of research on metformin, this article merely aims to condense the most important findings that may support or refute metformin’s benefits on longevity extension.

While there is incredible hype around its potential use as a so-called anti-aging therapy, it’s important to note that dosage matters, and that taking metformin at the same time as doing vigorous exercise may not be advisable.

In my view, some of the most important benefits of metformin might be mediated via bioelectricity.

As the field of bioelectricity grows, it would be really interesting to explore whether some of the positive effects observed by metformin therapy are due to its involvement in bioelectrical signaling.

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