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Life Extension Magazine

Life Extension Magazine November 2010
Reports

The Drug Virtually Everyone Should Ask their Doctor About

By Julius Goepp, MD

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.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

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

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