Life Extension

Metformin, A Breakthrough in Life Extension Research

As we already covered before, 2016 shows a lot of promise to be a great year for life extension research. One of the most interesting studies planned for this year is the TAME trial[1] (Targeting Aging with Metformin), a study that will test the use of aforementioned compound as a longevity drug in older adults who have cancer, heart disease, or cognitive impairment (or are at risk for these diseases).

What is it, exactly?

Metformin 3d skeleton
Metformin 3D structure

Metformin, also known as Glucophage ®, is an anti-diabetic drug that works by suppressing glucose production in the liver. Unlike the majority of diabetes drugs, however, it does not cause hypoglycemia (low blood sugar), even when given to non-diabetics.

Metformin is a drug of the biguanide class. As such, it resembles the compounds guanidine and galegine, found in the Galega officinalis plant (aka goat’s rue). Goat’s rue was known to have anti-diabetic activity since ancient times, but it proved too toxic to use.

The beginning of the history of metformin, however, has almost nothing to do with type 2 diabetes, but with an even worse disease: malaria.

History of Metformin

Cinchona officinalis bark
Harvested bark of Cinchona officinalis

Malaria is a disease caused by a parasitic microorganism of the Plasmodium species. The typical treatment for malaria before the advent of synthetic drugs was quinine, an alkaloid extracted from the bark of the South American tree Cinchona officinalis.

Quinine was expensive, and some parasites became resistant to it. Furthermore, the drug was imported from Java and the supply was unpredictable. In the 1930s, researchers began to discover and synthesize alternatives to quinine. A chemist named Francis H. S. Curd started investigating pyrimidine analogs at the ICI laboratories at Blackley, Manchester, after he noticed that some drugs with mild antimalarial activity had a pyrimidine ring in their structure.

Goat's rue
Goat’s rue

A number of compounds were synthesized and tested on malaria-infected chicks. Some of them were also tested on humans, but they proved too toxic for clinical use. Nonetheless, Curd persisted on in his research, and he figured out that using only a portion of the pyrimidine structure could potentially minimize toxicity while maximizing antimalarial effects. Paludrine, the fruit of Curd’s successful hypothesis, was synthesized in 1945. It is also interesting to note that part of Paludrine’s structure closely resembled galegine, the active component in goat’s rue mentioned above. Animal studies conducted two years after Paludrine’s discovery established that it was able to cause a small decrease in blood glucose. At the same time, in the Philippines, molecules of the same biguanide class were used by Dr. Eusebio Garcia, a local expert in infectious diseases. He noticed that flumamine, a guanidine analog, cured malaria in addition to lowering blood sugar levels.

The real breakthrough came with the work of French diabetologist Jean Sterne. While working at Aron Laboratories in Paris, he was prompted to action by Garcia’s report on flumamine. In collaboration with Denise Duval and others, he evaluated the anti-diabetic effect of flumamine in animals. It showed a powerful glucose-lowering effect which led him to coin the name Glucophage ®, meaning “glucose eater”. He published his results in 1957.[2]

Flumamine eventually became metformin and, in 1962, the first major clinical trial that tested metformin’s efficacy in type 2 diabetes was published.[3] 39 subjects were involved in the study, with almost all of them being over 30 years old. The study came to the following conclusions:

  • of the 39 patients, 14 showed satisfactory control of the disease with metformin
  • another 6 showed some improvement if the metformin was combined with low-dose insulin or another oral anti-diabetic agent
  • ‘pancreatic’ diabetics (now known as type 1 diabetes) did not respond to the treatment
  • treatment was with 1–3 grams of metformin per day, given as three divided doses, titrating up slowly and limited by the emergence of certain side effects.

Metformin was not the only biguanide anti-diabetic discovered in the 1930s. Phenformin and Buformin, used respectively in America and Europe, were actually stronger in anti-diabetic activity and had been the drugs of choice for type 2 diabetes up until the 70s, when they were banned after an ever-increasing number of deaths by lactic acidosis. Because metformin was seen as closely related to these two drugs, metformin’s public image was damaged. Although metformin hardly ever causes lactic acidosis, its damaged reputation meant it would take longer to catch on.

The next few decades saw a steady accumulation of data concerning metformin’s effectiveness and safety. One study, in particular, helped establish Glucophage ® as a safe and effective treatment for diabetes. The United Kingdom Prospective Diabetes Study, conducted from 1977 through 1997, effectively gave scientific evidence that metformin increases the lifespan of patients with obesity and type 2 diabetes.[4] Patients treated with metformin also had less incidence of heart attacks when compared to those treated with insulin or other diabetes drugs.

The Food and Drug Administration (FDA) of the United States approved metformin in 1994, which prompted its ascent as a popular diabetes drug in America. The patents covering metformin expired in 2002, which allowed it to be produced and sold inexpensively as a generic drug.[5]

New uses for an old drug


fight cancer with metforminEven though the research on Metformin as a cancer prevention tool is still in its infancy, it appears to be very promising. Metformin and other biguanide medications have been increasingly investigated for their chemopreventive (cancer-preventive) and antineoplastic (tumor growth-inhibiting) properties. There have been various studies conducted on lab animals that investigate metformin’s ability to reverse or prevent tumor growth. One meta-analysis on the subject reported that metformin’s effects on cancer have been tested on 17 different organs in various strains of rats, mice, and hamsters. Some studies investigated its effects on naturally-occurring cancer while others investigated how it affected cancer induced in the lab by 16 different chemical classes of carcinogens. In other words, metformin’s anticancer effects were studied under a wide variety of unique and nuanced cases of tumor growth. Many different dosing regimens and routes of administration were also tested.[6] In the majority of cases (86%) the treatment with metformin and other biguanides led to inhibition of carcinogenesis. No cases of stimulation of carcinogenesis by the antidiabetic biguanides were ever detected.

While the mechanism of action for the chemopreventive activity of Metformin is not entirely clear, it is likely caused by the activation of AMPK-dependent and AMPK-independent pathways, in addition to energy metabolism aberration, cell cycle arrest, apoptosis or autophagy induction,[7] as well as mTOR signaling inhibition.[8]

Life Extension

In April of 2003, researchers at Biomarker Pharmaceuticals in California studied the effects of metformin on aging processes and longevity. The researchers found that metformin actually mimics the anti-aging effects of caloric restriction. Caloric restriction is a type of dietary method that involves consuming a significantly reduced amount of calories while still consuming proper amounts of essential vitamins and nutrients. This method has been touted by some to slow the aging process and extend lifespan. When tested on mice, metformin appears to induce a change in gene expression that is identical to that caused by a CR diet. This change in gene expression has the potential to extend animal life spans by 20 percent. Metformin is the first medication that has been discovered to mimic the effects of a CR-induced lifespan extension.[9]

Another study published in the AGING Journal showed that female mice treated with metformin from an early age lived longer and had fewer tumors. These effects were not seen in aged mice[10]

Contraindications and Side effects

Metformin is a relatively safe drug. As said before, it can be taken by non-diabetics as long as the dose does not exceed 1500-1700 mg. A good idea is to check blood glucose levels. It’s not advised to take Glucophage ® should the blood glucose levels be equal or lower than 80mg/dL.

Metformin should not be used in those with liver disease, kidney problems or lung disease, and any other condition that could increase the risk of lactic acidosis.

Long-term use of high doses of Metformin may cause Vitamin B12 deficiency[11], especially in those who do not consume animal products (vegetarians and vegans). The amount of B12 in a multivitamin is generally not enough to correct the deficiency[12]. It is therefore a good idea to supplement Vitamin B12 when taking Metformin.

Even though it doesn’t have serious interactions, be sure to check the Metformin page on or the patient information leaflet.

The most common adverse effect are related to the gastrointestinal system, and may include diarrhea, cramps, nausea, vomiting, and increased flatulence. To avoid these side effects Metformin should be started at the lowest dose (500 mg) and slowly increased to the desired dose.


Metformin has been a revolutionary drug for diabetes, and new research on biguanides shows that these drugs may enhance lifespan as well as prevent cancer. While it’s still a bit early to recommend metformin to every >50 years old, (or subjects in high-risk populations, like smokers), we’re finally getting closer to a real breakthrough in life extension research.

More research is needed in order to understand the correct dosage and efficacy of Metformin in humans.

References   [ + ]


Is Berberine the New Resveratrol?

There are very few supplements that have a list of potential benefits as impressive as berberine. Despite the fact that berberine is not all that well known compared to many other supplements, it is extremely well researched. While not all of these benefits are guaranteed to occur for every single user, berberine has been found to

  1. Reduce inflammation
  2. Improve gastrointestinal health
  3. Reduce glucose production in the liver
  4. Improve markers of insulin resistance
  5. Lower cholesterol
  6. Lower oxidative stress
  7. Help in losing body fat
  8. Slow down aging
  9. Suppress chemical-induced carcinogenesis, clastogenesis, tumor promotion and tumor invasion
  10. Exert antiarrhythmic effects
  11. Exert anti-microbial activity against a wide range of microorganisms.
  12. Exert minor antidepressant effects, as well as work in a synergistic fashion with existing antidepressants

While this list of touted benefits is certainly impressive, berberine also carries with it a number medication interactions, which must be noted with caution (more on this later).

What is Berberine?


Berberine is an isoquinoline alkaloid and ammonium salt of a bright yellow color that is found in and extracted from a variety of plants from the genus berberis, as well as Coptis chinensisPhellodendron amurense, and Hydrastis canadensis (Goldenseal) and many others. These plants have a history of being used in both traditional Chinese Medicine and Indian Ayurveda as an anti-microbial agent. Berberine appears to be effective in fighting bacteria, fungi, and protozoa. [1] However, these traditional uses of berberine barely scratch the surface of its full capability.

When berberine is ingested orally, it has a relatively low bioavailability of 5% or less. [2] Berberine increases the action of P-Glycoprotein, a substance which actually makes berberine more difficult for the intestines to absorb. Because of this, taking a P-Glycoprotein inhibitor (such as Milk Thistle) can possibly make smaller doses of berberine more effective.[3] Another option is to take Berberine with Coconut oil that contains a fatty acid known as Sodium Caprate which significantly increases the absorption and the efficacy of Berberine.[4][5]

AMPK Modulation

One of berberine’s main mechanisms of action is its ability to activate an enzyme called Adenosine Monophosphate Kinase (AMPK). AMPK is crucial for maintaining energy homeostasis in cells. It is responsible for regulating glucose and other nutrients by sensing their concentrations within cells. [6] The activation of AMPK caused by berberine has multiple different effects. First, the AMPK activation causes an increased uptake of glucose into adipocytes (fat cells). This is one of the major methods through which berberine reduces glucose levels in the blood.[7] In fact, berberine’s antidiabetic effect is so effective that it is regarded as one of the few supplements to be as strong as a pharmaceutical drug. When taken correctly, berberine can be as effective (or even more effective[8] as the popular type II diabetes drug metformin.[9]

Molecular structure of BerberineBerberine also appears to have various positive effects on the heart and the cardiovascular system as a whole. Activated AMPK located in liver cells causes an inhibition of cholesterol and triglyceride synthesis.[10] This change is also linked to a lowering of low-density lipoproteins (“bad” cholesterol) and raising of high-density lipoproteins (“good” cholesterol). Additionally, berberine can lower the levels of LDL by stimulating the synthesis of LDL receptors, which are responsible for removing LDL from the blood.[11] The activation of AMPK induced by berberine also appears to inhibit the synthesis of lipids and lower triglyceride levels, which is useful for individuals who are attempting to lose weight.[12]

In one study, reperfusion (oxidative stress) was induced in rats who had been pre-treated with berberine. The rats treated with berberine displayed significantly less heart damage than those who had not been treated.[13] One study conducted on 24 overweight or obese subjects concluded that berberine was able to reduce blood pressure significantly more than placebo. [14] These effects of berberine—the inhibition of LDL cholesterol and triglyceride synthesis, increase in HDL cholesterol, decrease in lipid production, protection from oxidative stress, and the decrease in blood pressure—all work together to contribute to berberine’s overall positive effect on heart health and weight loss. But that’s not all…

Anti-aging & Anti-cancer

There is some early research evidence that seems to suggest berberine’s efficacy as telomerase inhibitor.[15] Telomerase is a protein that is intricately linked with cell proliferation and the life cycle of cells. Telomeres (the region that telomerase acts upon) are a portion of DNA sequences located at the ends of chromosomes that keep them from deteriorating.

Essentially, the inhibition of telomerase by berberine has potential applications in the area of life extension & longevity as well as a chemopreventive supplement or in conjunction with existing cancer treatments to increase their efficacy.[16]

fight cancerBesides telomerase inhibition, berberine has also been found to suppress the growth of a wide variety of tumor cells[17][18], including breast cancer,[19] leukemia[20], melanoma,[21] epidermoid carcinoma, hepatoma[22], pancreatic cancer[23], oral carcinoma, tongue carcinoma[24], glioblastoma, neuroblastoma[25], prostate[26][27][28] and gastric carcinoma.

Mental Health

Berberine also exhibits minor to moderate antidepressant effects. One study conducted on mice discovered that berberine administration reduced the immobility time of mice in a swim test, which is indicative of antidepressant effects. The same study also concluded that berberine caused significant increases in the levels of dopamine, serotonin, and norepinephrine in the whole brain. It was also discovered that berberine works synergistically with certain antidepressant medications, such as fluoxetine, imipramine, tranylcypromine, and venlafaxine.[29]

New studies suggest berberine may have a potential for inhibition and prevention of Alzheimer’s disease through inhibition of β-amyloids pathways and cholinesterase[30] and through antioxidant capacities. Berberine derivatives are currently being developed as potent acetylcholinesterase (AChE) inhibitors.[31]

As a PCOS treatment

In a 2012 human study[32], 89 Chinese women of reproductive age who met the diagnostic criteria for polycystic ovarian syndrome (PCOS) and insulin resistance, were recruited and prescribed the anti-androgen compound cyproterone acetate (2.0 mg/day) in a combined oral contraceptive pill with 35 mcg ethinyl estradiol, taken in a cyclic fashion. They also received advice from a nutritionist to limit dietary fat and carbohydrates without restricting calories.

They were then assigned to one out of three treatment groups:

  1. Berberine hydrochloride, 500 mg 3 times/day (n=31)
  2. Metformin, 500 mg 2 times/day for the first week, then 3 times/day for the remainder of the study (n=30)
  3. Placebo tablet 2 times/day (n=28)

Results of the study were:[33]

  • After 3 months, all the treatment groups showed a significant reduction in body weight and BMI.
  • Waist circumference and waist-to-hip ratio were reduced in all 3 groups. However, the berberine group showed a significantly greater reduction in these measures.
  • All 3 treatment groups showed a significant reduction in fasting insulin. However, in the placebo group, fasting plasma glucose and fasting glucose/insulin ratio remained unchanged.
  • Fasting plasma glucose decreased and fasting glucose/insulin ratio increased in the berberine and metformin groups. There was no significant difference between them.
  • The berberine and metformin groups showed comparable changes in total testosterone and free androgen index, which were significantly greater than placebo. However, sex hormone–binding globulin increased significantly in the berberine group when compared with both metformin and placebo.
  • All 3 groups had reductions in total cholesterol and triglycerides. The berberine group had a significantly greater decrease in triglycerides, total cholesterol, and LDL (“bad” cholesterol”), and a significantly greater increase in HDL (“good” cholesterol) when compared to metformin.
  • Adverse effects were minimal and fewer compared to metformin. Nine subjects who received metformin complained of transient abdominal discomfort including nausea, vomiting, mild diarrhea, and flatulence, while 3 who received berberine complained of a bitter taste in the mouth.

As a result of this study, the researchers conclude that berberine may prove a viable alternative to metformin in optimizing the health outcomes of women with PCOS.
Another study[34] on 102 anovulatory Chinese women was published in 2015 found that administration of berberine alone may improve the menstrual pattern and ovulation rate in anovulatory Chinese women with polycystic ovary syndrome, as well as decrease sex hormone binding globulin, insulin resistance, total cholesterol, triglycerides and low-density lipoprotein cholesterol in normal weight polycystic ovary syndrome women.

Side Effects & Interactions

Berberine is absorbed slowly by the intestine, meaning that high doses can cause diarrhea and cramping. For this reason, berberine is typically taken in various smaller doses throughout the day.

In terms of interactions, the most noteworthy is the potential interaction with macrolide antibiotics like azithromycin (Zithromax) and clarithromycin (Biaxin). The interaction between the two has the possibility of causing cardiotoxicity. Berberine also inhibits enzymes CYP2D6 and CYP3A4 which has the potential to affect how many other drugs are metabolized by the body.[35] For this reason, it is very important to discuss berberine supplementation with a healthcare professional to ensure no dangerous interactions will take place.

Goldenseal vs Berberine Hcl

berberine supplement
Berberine hydrochloride powder

The two most common ways to supplement Berberine are to take either Berberine hydrochloride (hcl) or Goldenseal root powder. This is extremely important and I’ll explain why.

Goldenseal, – which contains a number of other compounds besides berberine – has been shown to cause DNA damage in prokaryotic and eukaryotic organisms[36] as well as promote liver cancer in rats.[37]

Therefore, I strongly advise against using goldenseal root and to take Berberine Hcl instead, the same way it was used in the PCOS studies. If you’re taking goldenseal supplements, stop taking them as soon as possible!


Berberine is certainly unique among supplements in the fact that it is equally as effective as some prescription medications. It also boasts a myriad of benefits that impact a variety of systems throughout the body. This article has only scratched the surface of the researched benefits of berberine. A collation of the large body of evidence concerning berberine can be found here for anyone who wants to learn more about this fascinating supplement. While there are some potential side effects and medication interactions, berberine is still well worth checking out. Berberine stands as a hidden gem among supplements – one that has the potential to greatly improve one’s quality of life.

Berberine Hcl can be bought relatively cheap at PowderCity and other supplement and vitamins shop.

References   [ + ]

1. Berberine at
2. Bioavailability study of berberine and the enhancing effects of TPGS on intestinal absorption in rats.
3. Effect of berberine on the pharmacokinetics of substrates of CYP3A and P-gp.
4. Sodium caprate augments the hypoglycemic effect of berberine via AMPK in inhibiting hepatic gluconeogenesis (2012)
5. Enhancement of Sodium Caprate on Intestine Absorption and Antidiabetic Action of Berberine (2010)
6. Effect of AMPK activation on muscle glucose metabolism in conscious rats.
7. Berberine inhibits PTP1B activity and mimics insulin action.
8. Berberine Compared to Metformin in Women with PCOS | Natural Medicine Journal
9, 35. Berberine at
10. Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine.
11. Berberine inhibits dyslipidemia in C57BL/6 mice with lipopolysaccharide induced inflammation.
12. Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine
13. Berberine attenuates ischemia-reperfusion injury via regulation of adenosine-5′-monophosphate kinase activity in both non-ischemic and ischemic areas of the rat heart.
14. Effect of berberine administration on metabolic syndrome, insulin sensitivity, and insulin secretion.
15. Human telomeric G-quadruplex: the current status of telomeric G-quadruplexes as therapeutic targets in human cancer.
16. Human telomeric G-quadruplex: the current status of telomeric G-quadruplexes as therapeutic targets in human cancer.
17. A systematic review of the anticancer properties of berberine, a natural product from Chinese herbs (2009)
18. Berberine and Coptidis Rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations (2009)
19. The alkaloid Berberine inhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell cycle arrest (2009)
20. Down-regulation of cyclin B1 and up-regulation of Wee1 by berberine promotes entry of leukemia cells into the G2/M-phase of the cell cycle (2006)
21. Different concentrations of berberine result in distinct cellular localization patterns and cell cycle effects in a melanoma cell line (2008)
22. Coptis chinensis inhibits hepatocellular carcinoma cell growth through nonsteroidal anti-inflammatory drug-activated gene activation (2009)
23. Berberine Inhibits Cell Growth and Mediates Caspase-Independent Cell Death in Human Pancreatic Cancer Cells (2010)
24. Berberine induced apoptosis via promoting the expression of caspase-8, -9 and -3, apoptosis-inducing factor and endonuclease G in SCC-4 human tongue squamous carcinoma cancer cells (2009)
25. Berberine inhibits human neuroblastoma cell growth through induction of p53-dependent apoptosis (2008)
26. Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells (2006)
27. Butanol fraction containing berberine or related compound from nexrutine inhibits NFκB signaling and induces apoptosis in prostate cancer cells (2009)
28. Berberine inhibits p53-dependent cell growth through induction of apoptosis of prostate cancer cells (2009)
29. On the mechanism of antidepressant-like action of berberine chloride.
30. Conformation-activity studies on the interaction of berberine with acetylcholinesterase: Physical chemistry approach (2009)
31. Synthesis, biological evaluation, and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors (2009)
32, 33. Effect of berberine on insulin resistance in women with polycystic ovary syndrome: study protocol for a randomized multicenter controlled trial
34. A Single Arm Pilot Study of Effects of Berberine on the Menstrual Pattern, Ovulation Rate, Hormonal and Metabolic Profiles in Anovulatory Chinese Women with Polycystic Ovary Syndrome
36. Genotoxicity of the isoquinoline alkaloid berberine in prokaryotic and eukaryotic organisms
37. Toxicology and carcinogenesis studies of goldenseal root powder (Hydrastis Canadensis) in F344/N rats and B6C3F1 mice