~ Nov 2010 The Drug Virtually Everyone Should Ask their Doctor About

By Julius Goepp, MD, Life Extension

With each passing year, fresh scientific evidence emerges to vindicate Life Extension®'s contention that aging humans can derive enormous benefit from an antidiabetic drug called metformin.

In 2010 alone, scientists at top-ranked institutions made landmark discoveries that broaden its use to combat degenerative disease.

The ability of metformin to help facilitate weight loss has long been known. What few doctors understand are the unique mechanisms by which metformin can prevent and even help treat certain cancers.

In a remarkable finding, a team of Swiss researchers found that diabetic women on a long-term metformin regimen (5 years or more) experienced a 56% reduction in breast cancer risk.1 It also slashed pancreatic cancer rates by 62% in diabetics and may cut lung cancer rates in smokers.2,3

In this article, a novel link between impaired glucose control and cancer is detailed. You will discover the growing list of cancers metformin may effectively combat, including those of the colon, uterus, and prostate. You will also learn of a striking connection between the anti-cancer mechanisms of metformin and calorie restriction.

Why Metformin Should Be Viewed Differently than Other Drugs

Many Life Extension members like to brag that they do not need to take any prescription drugs. Given the lethal side effects posed by so many FDA-approved medications, avoiding them whenever possible makes sense.

Metformin is an exception! Its broad-spectrum anti-aging properties make it a drug that most longevity enthusiasts should seriously consider asking their doctors about.

Since it long ago came off patent, metformin is a super-low cost generic that everyone can afford.

Metformin Was Originally a Botanical Compound

Although it is sold as a prescription drug today, metformin has a long history as a botanical compound. It was originally derived from the French lilac (Gallega officianalis), which has had a place in folk medicine for hundreds of years.4,5

After decades of neglect in the 20th century, metformin was rediscovered during the acceleration of the global epidemics of obesity and type 2 diabetes. Metformin was approved by the FDA as a treatment for type 2 diabetes in 1994, and it became the most widely prescribed drug for this disease.6

Beginning around 2002, a series of epidemiological studies revealed a remarkable trend: diabetic patients taking metformin were less likely to die compared to diabetics using other forms of therapy, including other oral glucose-lowering drugs or insulin.7,8 The earlier studies also demonstrated specific benefits in protecting against cardiovascular diseases.9,10 By 2005, evidence from large, population-based studies was becoming clear: people taking metformin for diabetes were significantly and reliably protected against the increased cancer risk posed by the diabetes itself.2,11-15 Why should this be? The answer lies in a hidden relationship between elevated blood glucose and cancer development.

Diabetics are predisposed to a terrifyingly broad range of cancers of the liver, pancreas, colon, breast, endometrium (uterine lining), kidney, and possibly other tissues.16-18 Scientists theorized that if ways to reduce chronic blood sugar elevations and other molecular consequences associated with weight gain were discovered, this would have a powerful impact in interrupting some of the pathways that lead to cancer. Metformin, it turns out, acts in a multitargeted fashion to accomplish precisely those effects.18,19

The simplest way to understand metformin's role in cancer prevention is to recognize that it is a powerful calorie restriction-mimicking drug.20 It acts to essentially "fool" the body into "believing" that it is in a calorie-restricted state, thereby switching on the same protective mechanisms that arise from calorie restriction itself.

Let's now see how all this biochemistry translates to genuine anti-cancer action.

Breast Cancer

Some of metformin's most compelling effects are in cancers of the reproductive system because it blocks the enzyme called aromatase, which can stimulate estrogen-dependent cancer growth.21 Breast cancer is the most common malignancy diagnosed in women.22 Fortunately, most varieties of breast cancer are proving to be especially susceptible to metformin prevention in the laboratory, and to metformin treatment in human patients, as shown by studies that have emerged over just the past two years.23

Metformin suppresses a specific cancer-inducing protein (human epidermal growth factor receptor 2, or HER2)24 that dramatically increases the risk of breast cancer.25 By suppressing HER2, which can stop cancers from developing in the first place, metformin halts cancer cells' reproductive cycle, preventing them from growing once they have developed.26

Via a different set of mechanisms, metformin selectively targets cancer stem cells, cells that resist chemotherapy drugs and can regenerate and cause relapse of the disease.27 In live animal studies, metformin suppressed breast cancers, especially in animals on a high-calorie diet.20 In a dramatic 2010 study, metformin extended the life span of mice with HER2-positive breast cancers, delayed the onset of tumor development, and inhibited the growth of implanted tumors.19

The combination of all these effects means that metformin is effective against many different types of breast cancers, including those that are estrogen receptor positive and negative, and those that express both normal and excessive amounts of HER2.28 Indeed, data appeared in 2010 that long-term (greater than 5-year) metformin use by humans is associated with a substantial (56%) reduction in risk for developing breast cancer as compared with no use of metformin.1

Human trials have already demonstrated that diabetic patients with breast cancer who receive metformin plus chemotherapy have a higher rate of complete remission than do those not taking metformin. Complete remission occurred in 24% of diabetic patients taking metformin, 8% of diabetic patients not taking metformin, and 16% of non-diabetic patients not taking metformin.29 And a 2009 study showed that metformin induced unique, multitargeted responses in so-called "triple-negative" breast cancer cells, which represent some of the most difficult-to-treat forms of the malignancy.30

All of these findings speak to metformin's tremendous potential as a true breast cancer chemopreventive agent—one that can and should be used long before any sign of cancer has appeared. Scientists from around the world believe that the time has come to leverage these effects in breast cancer chemoprevention and treatment.22,23,31,32


What You Need to Know: Metformin
  • lose links between diabetes and cancer have been recognized for more than a century, but the causative mechanisms have only recently been clarified.

  • Diabetes and even undetected chronic elevations in blood sugar (insulin resistance) lead to tissue damage and increased insulin levels which can initiate and promote cancer in many tissues.

  • Metformin is a safe and widely-prescribed drug approved for use in type 2 diabetes; it is also a powerful calorie restriction-mimicking drug.

  • Metformin's calorie restriction-like actions include activation of a powerful and ubiquitous metabolic sensor called AMPK.

  • Activation of AMPK and its consequences subject cancer cells to unique metabolic stresses not experienced by healthy tissues, promoting death (and even preventing development) of cancer cells early in the cancer development process.

  • Metformin also independently inhibits an age-accelerating complex called mTOR that is implicated in cancer development.

  • While existing mTOR-inhibiting drugs are highly toxic, metformin inhibits mTOR without discernible side effects.

  • Metformin's other multitargeted anticancer effects combine with AMPK activation to suppress cancer throughout the body.

  • Metformin-induced protection has been demonstrated in cancers of the breast, endometrium, prostate, pancreas and colon, and will likely prove effective in virtually all cancers.

  • A serious calorie restriction-mimetic regimen should include metformin along with other proven nutraceuticals to optimize protection against cancers throughout the body.



Endometrial Cancer

Cancer of the endometrium, or lining of the uterus, is the most common genital malignancy. It has multiple risk factors, among them obesity, insulin resistance, and diabetes.33 An early sign of cancerous change is endometrial hyperplasia. Standard therapy for endometrial hyperplasia is treatment with progestogens (progesterone-like hormones), which can restore the endometrium to its normal state. In 2003, researchers at the Mayo Clinic reported a single case study of a woman whose endometrial hyperplasia had failed to respond to progestogen treatment, and who was then given metformin (she was not diabetic).34 One month after initiation of treatment, the patient's endometrium had returned to its normal state.

In 2010 scientists learned that metformin is a potent inhibitor of endometrial cancer cell proliferation, acting to arrest the cancer cells' reproductive cycle, inducing cell death through apoptosis, and decreasing gene expression of an enzyme complex called human telomerase reverse transcriptase (hTERT) that contributes to unregulated cell replication.35 Many of these effects were triggered by metformin's activation of the AMP-protein kinase (AMPK) complex, and are identical to those induced by calorie restriction.35 Metformin mimics the benefits of a hormone called adiponectin in activating AMPK-dependent growth inhibition in prostate and colon cancer cells.

Based on these observations, other gynecological researchers have begun to use metformin as part of a "conservative" approach (using fewer, less-invasive procedures) to their management of endometrial hyperplasia and endometrial cancer.3

Prostate Cancer

Metformin mimics the benefits of a hormone called adiponectin in activating AMPK-dependent growth inhibition in prostate and colon cancer cells.

Prostate cancer is the most-commonly diagnosed cancer in men. Insulin resistance, which triggers rising levels of insulin and insulin-like growth factors (IGFs) substantially increases disease risk.37,38 For that reason, reducing plasma insulin and IGF levels are significant goals in prostate cancer prevention and treatment, and metformin is increasingly being recommended in those roles.37

Metformin mimics the benefits of a hormone called adiponectin in activating AMPK-dependent growth inhibition in prostate and colon cancer cells.38 This helps solidify our understanding of the relationship between obesity, in which adiponectin levels are low, and cancer development.

Metformin also acts by blocking the prostate cancer cells' reproductive cycle by decreasing levels of a cancer growth-promoting protein (cyclin D1), and at the same time increasing production of a protein (p27) that inhibits the cell division cycle.39 As an aside, it is p27 that is also enhanced (upregulated) by healthy levels of vitamin D, the omega-3 fatty acid DHA, and silibinin—one of the active agents in milk thistle.40-42 These results testify to metformin's ability to attack cancers from multiple directions at once.

Still another angle from which metformin suppresses prostate cancer is to literally starve the malignant cells of energy, capitalizing on metabolic vulnerabilities unique to cancer cells and absent in healthy cells. Stunning results appeared in early 2010 showing that metformin, in combination with the metabolic agent 2-deoxyglucose, dramatically depletes prostate cancer cells' stores of energy-rich ATP molecules.43 In fact, the treatment led to a 96% reduction in malignant cells' viability, with only moderate effects on healthy prostate cells. The treatment also triggered a switch from survival processes to cell death in the malignant cells.

These laboratory findings took on profound meaning in a large human study of men with prostate cancer and their use of metformin.44 Among 1,001 men with prostate cancer and 942 cancer-free controls, metformin use was significantly more common in the control patients, resulting in a risk reduction of 44%. This finding is especially powerful considering that men taking metformin in this retrospective study were much more likely to have been diabetic, and so their risk for cancer could be expected to have been higher.

Pancreatic Cancer

Pancreatic cancer is one of the most lethal human diseases, with a nearly-100% fatality rate, and experts are desperate for new biochemical targets that will help control this disease.45 One such novel target that has been proposed is IGF-GPCR, an interaction between IGF receptors and a powerful group of signaling proteins called G protein-coupled receptors (GPCR). Metformin administration disrupted the IGF-GPCR interaction and thereby significantly decreased the growth of pancreatic cancer cells grafted into susceptible mice.46

Metformin also triggers pancreatic cancer cell death by apoptosis by activating caspase, a "death signaling" or "executioner" molecule.47

These laboratory findings help explain the remarkable protective effects of metformin in preventing pancreatic cancer in living humans. A large hospital-based case-control study of 973 patients with pancreatic cancer and 863 healthy controls demonstrated a dramatic risk reduction of 62% in diabetic patients who had taken metformin compared with those who had not.2 The difference wasn't related solely to reduction in blood sugar, since diabetic patients who had taken insulin or insulin-promoting drugs enjoyed no similar protection. This study, of course, could also be interpreted to show how insulin-promoting drugs and insulin itself increases cancer risk. Life Extension has long warned about the carcinogenic risks associated with elevated insulin levels. Fortunately, another benefit of metformin is reducing insulin and glucose levels via several mechanisms.

Fighting Obesity and High Blood Sugar

Metformin, originally developed as a simple glucose-lowering drug for type 2 diabetics, is emerging as one of the few true "wonder drugs" of the century. Metformin improves glycemic control, helps prevent and treat obesity, and reduces insulin resistance. And those very characteristics are intimately related to metformin's astonishing anti-cancer properties. Here's an overview of metformin's myriad, multi-targeted effects on obesity and its consequences.

Metformin is first-choice treatment for type 2 diabetes, with especially powerful effects on obese patients with high insulin levels.53 But metformin is emphatically not just for diabetics. Metformin results in weight loss and improves insulin resistance, even in non-diabetic individuals.54,55

We know that poor glycemic control leads to chronic diseases of aging. Reducing blood glucose levels thus has multiple benefits related to general health.

By enhancing insulin sensitivity, metformin protects obese patients from endothelial dysfunction and the cardiovascular disorders that result.56 Metformin also decreases secretion of a variety of damaging cytokines that, unopposed, light inflammatory fires throughout the body.57

And although metformin was long thought to exert its primary effects in the liver and other non-neurological tissues, the drug also has an appetite-suppressing effect on the central nervous system.58 This all adds up to powerful potential in combating excess body weight.

Two challenging populations provide the best arena for demonstrating metformin's anti-obesity effects. Women with polycystic ovarian syndrome (PCOS) have abnormal sex hormone profiles that can lead to significant obesity despite aggressive dieting. And patients on the newer, second-generation antipsychotic drugs virtually all gain weight, and many develop the metabolic syndrome even at very young ages. Metformin has shown dramatic effects in reducing body weight, BMI, insulin resistance, and other manifestations of disordered metabolism in both of these populations.57-60

There's hardly a body system that doesn't benefit in some way from metformin's profound impact. The case of cancer provides a perfect example. We now understand that obesity and its fallout on insulin levels and inflammation are important risk factors for many cancers.61

By promoting weight loss, metformin provides documented risk reduction and has crucial direct actions on some of the fundamental molecular pathways that lead to cancer. Those effects are themselves related to metformin's calorie restriction-mimicking effects.62 Thus, we can see that metformin reduces the risk of obesity and fights cancer by closely interrelated mechanisms, promoting actual weight loss while also triggering the beneficial effects of calorie restriction at the cell and molecular levels.

In a recent example, a team of researchers at Stanford found that metformin significantly decreases body mass index in obese, non-diabetic adolescents. This marks a promising new advance in the battle against childhood overweight and obesity, which now afflicts almost one third of all children in the United States.63

Colon Cancer

Colorectal cancers are major public health problems, being the second most common cancers in developed countries.48 As with other malignancies, colorectal cancer risk is increased in diabetics, and there is a growing body of evidence that advanced glycation end products (AGEs) and insulin-receptor interactions are involved in initiation of these common tumors.48,49 Naturally, these findings have piqued scientists' interest in using metformin, which decreases glucose and insulin levels, to prevent colorectal cancer.

Colorectal cancers are among those malignancies most closely associated with obesity.38 Obese individuals are deficient in the protective hormone adiponectin, which activates tumor-suppressing AMPK.38 Metformin, by independently activating AMPK, may short-circuit this deficiency and help to reduce its impact on colorectal cancer risk.38

Metformin has at least one additional pathway by which it prevents colorectal cancer. It is related to the close connection between colon cancer and too many calories. Canadian scientists placed mice on either a normal or a high-calorie diet, and then injected them with viable colon cancer cells.50 Seventeen days later they examined the tumors that the animals had developed. Tumors from mice on the high-calorie diet were twice the volume of those from normally-fed mice, and their size correlated with elevated insulin levels. Metformin treatment blocked the effect of a high-calorie diet, reducing insulin levels and slowing the growth of tumors. Tumors from metformin-treated mice also showed increased rates of cell death by apoptosis compared with those from untreated animals.

How Metformin Protects Against Cancer

Like calorie restriction, metformin activates an important molecule called AMPK (adenosine monophosphate-activated protein kinase) which senses cellular energy status.64 AMPK is activated by a variety of cellular stresses including decreased energy availability—a known result of calorie restriction. It also modulates multiple metabolic pathways.65

In the liver, AMPK reduces production of new glucose molecules, indirectly reducing levels of insulin and insulin-like growth factors (IGFs).66 That's how metformin works to correct type 2 diabetes. But throughout the body, AMPK activation stimulates fatty acid oxidation, enhances insulin sensitivity, alleviates hyperglycemia and hyperlipidemia, and inhibits prolinflammatory changes.67 Those effects alone could be expected to have substantial anti-cancer benefits, in light of what we know about the role of glucose, insulin, IGFs, and inflammation in cancer development.68

But there's more. Cancer cells have metabolic characteristics different from normal cells, making them vulnerable to metabolic manipulation (as opposed to chemotherapy's imprecise, wholesale poisoning of all body tissues).69 So in cancer cells, AMPK activation triggers a unique cascade of molecular events that collaborate to suppress cancers.67,70 AMPK activation suppresses cancer cell proliferation; it does this by blocking the gene expression of specific cancer-promoting proteins.30,66 AMPK activation also breaks a critical link between obesity and postmenopausal breast cancer by blocking estrogen production within the breast tissue.21

Laboratory studies have now demonstrated that metformin's AMPK activation, and reduction of IGF, can suppress development and growth of cancer cells from breast, ovary, pancreas, and many other tissues.45,62,71,72 One of the most heartening findings has been the effectiveness of metformin against even some of the most aggressive forms of breast cancers, which disproportionately affect younger women.23,66

Lung Cancer

More men and women die from lung cancer than from any other malignancy. In 2006, lung cancer caused more deaths than breast cancer, colon cancer, and prostate cancer combined.51 Clearly, new solutions to fighting lung cancer are greatly needed. Emerging research suggests that metformin may offer hope in combating this deadly disease.

A New Pathway for Cancer Reduction

There is late-breaking news that there is now an additional mechanism by which metformin can reduce the risk of cancer and metabolic disorders.

A molecular complex called mammalian target of rapamycin (mTOR) functions as a "metabolic integrator," receiving inputs about energy and stress levels and translating them into cellular actions.73-75 And when mTOR signaling goes awry, it triggers numerous events, including those leading to a variety of cancers.76 Aberrant mTOR activation, in fact, has now been added to the list of biochemical abnormalities that contribute to many of the chronic diseases of aging.77,78

Calorie restriction inhibits the action of mTOR, thereby reducing the risk of many diseases of aging.79,80 Scientists have known for a decade that metformin inhibits mTOR in a fashion similar to calorie restriction. But until recently they'd thought that the mTOR inhibition was simply another result of metformin's AMPK activation.46,81,82

George Thomas, PhD, scientific director of the Metabolic Diseases Institute at the University of Cincinnati83 and his colleagues have discovered that metformin efficiently inhibits mTOR—completely independent of its effect on AMPK.76 That supports and extends the few previous studies that had shown an AMPK-independent action for metformin.84-87 Together these findings have tremendous implications; Thomas himself recently said this, "Metformin is already prescribed to 100 million people worldwide, and our study raises the question, ‘Could this drug be used even more widely?'"83

The fact is that mTOR inhibitor drugs have been in use for at least 5 years, primarily in managing transplant rejection, and recently in certain forms of cancer.88-90 But these drugs, based on a failed antifungal drug called rapamycin (also called sirolimus), have tremendous toxicity. Fortunately in mid-2010, a lab study demonstrated greater anticancer effects with metformin than with rapamycin.91

The discovery of metformin's direct mTOR-inhibitory effects, then, means this dramatically new mechanism of action is available to thousands of people who would have had no options other than facing the toxicity of the traditional mTOR inhibitors.

In a recent study, scientists examined the effects of metformin on an experimental form of lung cancer that is especially aggressive in obese subjects with high blood sugar. Animal subjects received either a control diet or a high-energy diet that typically leads to weight gain and insulin resistance, and selected subjects received metformin in their drinking water. After three weeks, the subjects were injected with lung cancer cells. Seventeen days later, animals on the high-energy diet had tumors that were twice the volume of animals on the control diet. Metformin significantly attenuated tumor growth in subjects consuming a high-energy diet. Metformin led to increased phosphorylation of AMPK and attenuated the increased insulin receptor activation association with a high-energy diet—both of which would be expected to decrease cancer proliferation.3

Additional research suggests that metformin may enhance the effects of radiation therapy in eradicating lung and other cancers.52

While further studies are needed, these findings suggest that metformin may offer promise in the fight against lung cancer.

Metformin May Help Treat Hepatitis C Infection

New research suggests that anti-diabetic drugs such as metformin and AICAR, currently used to fight obesity, may benefit patients with hepatitis C by preventing replication of the virus in the body.92 Hepatitis affects about 3% of the world's population, many of whom will develop cirrhosis or liver cancer.

Currently there is no vaccine or cure.

Metformin and AICAR work by stimulating the cellular energy-regulating enzyme AMPK, which the hepatitis C virus represses in order to replicate. When hepatitis C-infected cells were treated with metformin, virus replication was halted, allowing cells to clear the infection.

Based on this finding, a clinical trial will begin shortly at the University of Nottingham to explore metformin's applications in the management of hepatitis C.

Summary

The list of cancers against which metformin is protective is growing rapidly, now including cancers of the prostate, pancreas, liver, lung, and other tissues.3,16,95,96 Since metformin acts by multiple pathways, most of which are fundamental to every kind of cancer, there's no reason to think that these results won't in fact be generalizable to every human malignancy.

The key fact about metformin is its ability, shared with other nutraceuticals but rare among other prescription drugs, to potently mimic the effects of calorie restriction. Metformin's calorie restriction-like effects trigger profound cellular changes in every mammalian tissue, activating tumor suppressing mechanisms while suppressing tumor activating mechanisms. By lowering chronic blood sugar levels and limiting lifetime exposure to insulin and insulin-like growth factors, metformin can directly reduce cancer risks related to these factors.

The wealth of evidence of metformin's anti-cancer activity is now expanding to include not only those with diabetes or pre-diabetic conditions, but also people who are apparently otherwise healthy. This means that anyone who is serious about a comprehensive approach to cancer prevention should give serious consideration to using metformin just as faithfully as they use other calorie restriction-mimetic supplements.

Those seeking to gain the longevity benefits associated with reduced glucose and insulin levels can benefit tremendously from metformin.

Who Cannot Use Metformin

Metformin has been associated with an increase risk of lactic acidosis, a rare but potentially fatal buildup of lactic acid in the blood. Since congestive heart failure, kidney impairment, and liver problems increase the risk of lactic acidosis, individuals with these conditions are advised against using metformin. People with metabolic ketoacidosis and people taking both gemfibrozil and itraconazole should not take metformin.93 Individuals with type 1 diabetes should also not take the drug. People who have recently suffered a heart attack or stroke and those who have recently undergone surgery or are severely dehydrated are more vulnerable to lactic acidosis.94 Consult with your doctor if any of these conditions applies to you or if you are pregnant, planning to become pregnant, or breastfeeding.

Lactic acidosis is a medical emergency. Symptoms include muscle pain, difficulty breathing, sleepiness, feeling extremely weak or tired, and abdominal pain with nausea, vomiting, or diarrhea.93

There have been some reports that metformin can decrease TSH levels in people with an underactive thyroid or Hashimoto's thyroiditis. These reports suggest that metformin may suppress TSH levels, perhaps without effecting thyroid hormone levels. However, more studies involving larger groups of people are needed before any conclusions can be made about metformin, TSH level, and thyroid hormone levels.97,98

As you read in last month's issue, optimal fasting glucose should be around 80 mg/dL. Metformin can help aging humans achieve these lower and healthier glucose levels. Typical doses are 250 mg to 850 mg taken before two or three meals each day. Refer to the box on the following page for information about who should not take metformin.

Metformin May Protect Smokers Against Lung and Colorectal Cancer

Two recent articles in the medical journal Cancer Prevention Research reveal that smokers may have a much lower risk of suffering lung cancer and colorectal cancer if they take the drug metformin.

Metformin is a popular drug used to combat diabetes type 2, however, two studies show it holds promise as an anticancer drug as well. A study conducted by the scientists at the National Cancer Institute, led by Dr. Philip Dennis, revealed a significantly lower lung cancer tumor rate in mice that were given metformin and exposed to a prevalent tobacco carcinogen.97 The mice injected with metformin had 72% fewer tumors.

A second study conducted by scientists in Japan revealed that non-diabetic individuals who took metformin had a considerably reduced rate of rectal aberrant crypt foci, a surrogate marker of colorectal cancer.98

References . . .


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