Metformin 850mg on a pharmacy shelf. Photo: By CareFusion Germany 326 GmbH (Own work) CC BY-SA 4.0

Can We Live to 120 On Metformin?

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Summary: Report on metformin and anti-aging medicine. To find out if metformin will extend lifespan, researchers are conducting a $65 million clinical trial of metformin as an anti-aging drug. Here’s what both sides of the metformin debate have to say.

A drug costing 5 cents could help us live longer, healthier lives.

Used for decades to treat type 2 diabetes, metformin is showing promise as an anti-aging drug. Researchers are looking into whether metformin holds the key to living longer — and the latest research has been favorable.

Metformin Has a Long History

What we know today as metformin, has a long history. It is the active ingredient in a plant known as French lilac or goat’s rue. Doctors have been prescribing it as an herbal remedy for centuries. Goat’s rue has been used since medieval times as a remedy for frequent urination, a telltale sign of diabetes. French physician Jean Sterne isolated the active compound from the French lilac in the 1950s. Today, we know that compound as metformin.

Metformin was introduced as a medication in France in 1957 and was approved by the FDA for treating type 2 diabetes in 1994, and in other countries decades earlier.  While the drug is primarily used to fight the epidemic of type 2 diabetes, it is used for other conditions, as well. The inexpensive generic is also used off-label to treat other conditions like gestational diabetes, prediabetes, and polycystic ovarian disease. A growing body of evidence shows that the drug prevents cancer, heart disease, and type 2 diabetes.

 

Using metformin as an anti-aging drug makes sense since it helps the body use insulin properly, lowering blood sugar. Metformin decreases glucose production in the liver, decreases intestinal absorption of glucose, and improves insulin sensitivity. Because metformin effectively lowers both blood sugar and insulin levels, it also reduces the risk of many other chronic degenerative diseases. Metformin also promotes weight loss.

Evidence on Metformin’s Anti-Aging Properties

The evidence on metformin and anti-aging has come from observational studies. The FDA doesn’t believe aging is a disease.  Nor are they convinced by the observational studies that metformin can slow down aging in the general population. To convince the FDA to consider aging as a treatable disease, researchers are a conducting a landmark clinical trial called Treating Aging with Metformin (TAME). The goal of TAME is to prove that both metformin and anti-aging drugs are topics worth further investment.

Dr Nir Barzilai in 2015 healthspancampaign interview.
Dr. Nir Barzilai talks about the TAME study, metformin, and anti-aging. Photo: HealthSpanCampaign.org.

 

Advocate for Metformin and Anti-Aging

Nir Barzilai, MD is the leading spokesperson for metformin and anti-aging science in general. Dr. Barzilai knows a thing or two about aging, as he is currently director of the Institute for Aging Research at the Albert Einstein College of Medicine. Dr. Barzilai is an expert on the genetics of aging, metformin and anti-aging medicine.

Wired reporter Sam Apple caught up with Dr. Barzilai and asked him about metformin and anti-aging in July of this year. After talking to Dr. Barzilai and other anti-aging researchers, the correspondent summarized the powers of metformin:

 “The metformin-takers tended to be healthier in all sorts of ways. They lived longer and had fewer cardiovascular events, and in at least some studies they were less likely to suffer from dementia and Alzheimer’s.”

“Most surprising of all, they seemed to get cancer far less frequently—as much as 25 to 40 percent less than diabetics taking two other popular medications. When they did get cancer, they tended to outlive diabetics with cancer who were taking other medications.” – Sam Apple

Barzilai’s Obsession With Metformin and Anti-Aging

Nir Barzilai, MD, has received acclaim for his work on metformin and anti-aging in general. He has been featured in a National Geographic documentary on aging, and in the Wall Street Journal, CNN.com, the New York Times, and the Washington Post.

Early in his career, Dr. Barzilai conducted a series of studies on centenarians, people who live to an unusually old age. The doctor discovered that centenarians died from the same chronic diseases as everyone else, but they developed them the at ends of their lives. In other words, they somehow managed to slow the aging process and compress the diseases of aging into their last years. Dr. Barzilai drew blood samples from hundreds of centenarians and studied their genetic code to find out what made them live longer than most. The researcher discovered anti-aging genes. Barzilai hopes to use the discovery as a basis for an anti-aging medicine for the general population. Until then, metformin is the leading anti-aging candidate and a favorite subject of Dr. Barzilai.

Metformin in Longevity Study (MILES)

Dr. Barzilai is an expert on metformin and its anti-aging properties. The researcher first studied the diabetes medicine in the late 1980’s while completing a fellowship at Yale University. Dr. Barzilai conducted an earlier study called the Metformin in Longevity Study (MILES). MILES was a pilot study that examined metformin’s anti-aging effects in older adults with prediabetes.

The MILES team wanted to see if metformin could restore the aging genes of older prediabetics to those of young healthy subjects. The researchers divided the study participants into two groups. They gave the test subjects 1700 milligrams of metformin daily and gave the others placebo. Barzilai’s team has already completed the MILES study, and are currently analyzing the results.

Taming Aging with Metformin (TAME)

Dr. Barzilai again entered the spotlight when he spearheaded the Taming Aging with Metformin (TAME) study, the world’s first clinical trial for an anti-aging drug. The Food and Drug Administration (FDA) has given the go ahead for TAME, a double-blind, placebo-controlled study.

Dr. Barzilai gave an interview in 2015 to Healthspan Campaign in which he expressed his excitement about metformin and its anti-aging powers. The researcher cited evidence that metformin delays the onset of many diseases of aging, including heart disease, cancer, and premature death.

As reported in the interview, TAME is the first test of an anti-aging drug. During the interview, Dr. Barzilai said TAME is a randomized controlled trial testing metformin’s anti-aging abilities on 3,000 healthy, nondiabetic seniors. The study participants will be followed for five years to test whether metformin can delay the chronic diseases of aging including cancer, cardiovascular disease, type 2 diabetes, cognitive decline, and premature death.

Barzilai has two expectations for the TAME study. First, for the FDA to accept aging as a treatable condition. Second, to demonstrate that metformin is a bonafide anti-aging drug. The TAME trial is a proof of concept which will show that both metformin and anti-aging medicines merit further attention. While metformin may not be the strongest anti-aging elixir, if the FDA approves it as a way to combat old age, it will pave the way for other anti-aging medicines.

Barzilai’s Essay On Metformin and Anti-Aging

In a 2016 essay in the journal Cell, Dr. Barzilai made a compelling case for metformin and anti-aging drugs. The respected researcher cited evidence showing that metformin prevents heart disease, diabetes, cancer and Alzheimer’s disease.

Citing as evidence, Barzilai referred to a massive observational study, the 2014 Bannister Study on metformin use. The landmark study got the attention of many in the medical and anti-aging community when it showed that, on average, type 2 diabetics taking metformin lived about the same number of years as people without diabetes.

An amazing result, because type 2 diabetics usually die ten years earlier than normal people. Even more remarkable was the finding that the older metformin-treated participants – those over the age of 70 –  lived longer their matched nondiabetic control group. The authors of the Bannister study also suggested that metformin may help ordinary people – those without diabetes – to live longer.

anti-aging cellular pathways intersect in complex ways.
Scientists are researching anti-aging pathways.

Anti-Aging Pathways

Before they can develop anti-aging drugs, scientists must first understand the complex aging process. Scientists believe there are many pathways involved in aging. As well there are anti-aging pathways that block the process. Once scientists have identified the exact aging pathways, they can develop drugs that block them. Several anti-aging pathways have already been identified. Known anti-aging interventions include changes in diet, such as fruit and vegetables, exercise and medications, including metformin.  While they have made great progress, anti-aging researchers have not reached a consensus on exactly how humans age.

Metformin’s Anti-Aging Mechanisms

While the evidence shows that metformin has anti-aging properties, no one has identified the exact mechanisms of action. The molecular mechanisms underlying metformin’s mode of action are complicated and remain a topic of debate. The molecular pathways affected by metformin and anti-aging mechanisms are complex and intersect at several points.  While scientists understand which pathways metformin effects; they do not fully understand how the drug impacts aging. They know that autophagy, inflammation, and cellular senescence all cause aging, but they are not quite sure how to block them.

Anti-aging metformin helps the blood.
Metformin has anti-aging effects on the blood. Photo: PDP

Metformin and Anti-Aging Effects On Blood Chemistry

As we grow older, we gain weight, and our blood sugar, insulin, cholesterol, and triglycerides levels rise. Metformin reverses these conditions. Metformin inhibits the production of glucose in the liver. This enables the pancreas to reduce the production of insulin which results in lower levels of blood glucose and insulin. Metformin increases insulin sensitivity, meaning the body uses insulin more efficiently. Metformin also decreases appetite and food consumption, causing weight loss. The anti-aging drug also decreases triglycerides and LDL-cholesterol levels.

Anti-aging metformin reduces insulin levels.
Anti-aging metformin reduces insulin levels in type 2 diabetics. Photo: Myriams-Fotos

Metformin and Anti-Aging Effects On Insulin

Excess insulin is damaging and is one cause of accelerated aging. Excess insulin causes damage to virtually all organs in the body, especially the kidneys, eyes, nerves, and blood vessels. Elevated insulin levels are incredibly pro-aging, they increase blood pressure, obesity, chronic inflammation, atherosclerosis, and Alzheimer’s disease. By lowering insulin levels, metformin reduces the incidence of these diseases.

Anti-aging metformin reduces blood sugar levels.
Anti-aging metformin reduces blood sugar levels in type 2 diabetics. Photo: Steve Buissinne.

Metformin’s Anti-Aging Effects On Blood Sugar

Sugar sometimes combines with proteins, rendering them nonfunctional. The process is called glycosylation and is one cause of aging. Because metformin lowers blood sugar levels, it reduces glycosylation and slows down the destruction of proteins throughout the body. Metformin is truly an anti-aging wonder.

In his essay Barzilai notes metformin’s anti-aging properties, writing:

“Metformin favorably influences metabolic and cellular processes closely associated with the development of age-related conditions, such as inflammation, autophagy and cellular senescence.”

Barzilai adds:

“Specifically for aging, metformin leads to decreased insulin levels, decreased IGF-1 signaling, inhibition of mTOR, inhibition of mitochondrial complex 1 in the electron transport chain, and reduction of endogenous production of reactive oxygen species (ROS) activation of AMP-activated kinase (AMPK), and reduction in DNA damage.”

Metformin Reduces Heart Disease

In his essay, Barzilai showed that metformin prevents heart disease in type 2 diabetics. Dr. Barzilai cited evidence shown by the 1998 United Kingdom Prospective Diabetes Study (UKPDS).  The UKPDS study compared metformin to other diabetes medications. Compared to other diabetes medications, the diabetics taking metformin had a reduced risk of all diabetes-related complications, including heart attack, stroke, and death.

After the UKPDS trial ended in 1998, the original participants were followed for another ten years. In 2008, the UKPDS team reported that metformin continued to work well since 1998, reducing all diabetes complications by 21%, including reducing the risk of heart attack by 33%, diabetes-related death by 30%, and lowering the risk of all causes of death by 27%.

Since 2008, metformin’s ability to prevent cardiovascular disease has also been confirmed by many other authors. Substantial evidence has built up over the years, based on research studies using human subjects, including the meta-analysis by Lamanna in 2011, as well as studies by lead authors Johnson (2005), Roumie (2012) and Hong (2013).

Metformin has been used off label to delay diabetes.
Metformin has been used off-label to delay diabetes.

Metformin Stalls Diabetes

Studies of prediabetics taking metformin have shown that the drug prevents type 2 diabetes.  Prediabetes is a precursor to diabetes, a condition in which a person has high blood sugar, but is not yet diabetic.

With a healthy diet and exercise, type 2 diabetes can be delayed or prevented. Overweight people are at risk of developing the disease unless they take steps to prevent it.

Metformin has been extensively studied as a prediabetes treatment. An extensive study called the Diabetes Prevention Program (DPP) showed that diet and exercise sharply reduced the odds that a prediabetic would develop type 2 diabetes. Metformin also reduced the risk, although less dramatically.

A related article provides more detail about metformin as a prediabetes treatment. Metformin is not yet fully approved for the prevention of diabetes in prediabetics. The use of metformin in prediabetics is considered an acceptable off-label use by the U.S. FDA.  Only a few countries, such as Poland, Turkey, and The Philippines, fully accept the practice.

Metformin Reduces Cancer Rates

In 2014, Gandini and colleagues published the strongest evidence to date that metformin prevents cancer. Up until that time, the evidence had been piling up, with dozens of studies linking metformin to reduced cancer rates. The Gandini team gathered all the evidence presented by 47 high-quality studies on the subject. The team pooled the results of the different studies in a massive collation effort called a systematic review, that covered more than 65,000 cancer cases in diabetics.

After averaging the results of the various studies, Gandini and colleagues showed that metformin usage reduced the rate of cancer by 31% and mortality by 34%.

A related article discusses how metformin prevents cancer in people with health conditions. A bit of caution is advised, although the evidence is strong, to date, all the research linking metformin with cancer has only been observational. Additionally, metformin has been shown to reduce cancer in type 2 diabetics, not in healthy people.

Other Viewpoints On Metformin and Anti-Aging

The naysayers point to the fact that metformin has not been tested in healthy people. While studies have shown that metformin prevents age-related diseases in diabetics, it has not been shown to work in healthy non-diabetics.

Take Home Message

  • Researchers aren’t sure if metformin will have the same anti-aging effects in non-diabetics. For confirmation, we have to wait on the results of the TAME and MILES trials.
  • Studies of type 2 diabetics and prediabetics show that metformin has many health benefits. Metformin use helps prevent diabetes in prediabetics. As well, studies show that type 2 diabetics using metformin have reduced rates of cancer and heart disease. The health benefits of metformin make it the world’s most popular type 2 diabetes medicine.

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References

Nir Barzilai, Jill P. Crandall, Stephen B. Kritchevsky, and Mark A. Espeland. Metformin as a Tool to Target Aging.  Cell Metabolism (2016) http://dx.doi.org/10.1016/j.cmet.2016.05.011. Available Online.

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New England Journal of Medicine 2002;346:393–403. Available Online.

Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. The Lancet 2009;374:1677–86. Available Online.

C. A. Bannister, S. E. Holden, S. Jenkins-Jones, C. Ll. Morgan, J. P. Halcox, G. Schernthaner, J. Mukherjee, C. J. Currie. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched non-diabetic controls. Diabetes, Obesity, Metabolism 2014. PMID: 25041462. Available Online.

Chin Cheng, Ching-Heng Lin,  Yi-Wen Tsai, Chia-Jui Tsai,  Po-Han Chou, Tsuo-Hung Lan. Type 2 Diabetes and Antidiabetic Medications in Relation to Dementia Diagnosis.  The Journals of Gerontology: Series A, Volume 69, Issue 10, 1 October 2014, Pages 1299–1305, https://doi.org/10.1093/gerona/glu073. Available Online.

Diabetes Prevention Program Research Group (2012). Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care 35, 731–737.

Mary E Tinetti, Gail McAvay, Mark Trentalange, Andrew B Cohen, Heather G Allore. Association between guideline recommended drugs and death in older adults with multiple chronic conditions: population based cohort study. doi: https://doi.org/10.1136/bmj.h4984, 02 October 2015. BMJ 2015;351:h4984. Available Online.

UK Prospective Diabetes Study (UKPDS) Group (1998). Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. Volume 352, No. 9131, p854–865, 12 September 1998. DOI: http://dx.doi.org/10.1016/S0140-6736(98)07037-8.  Available Online.

Giovanni Anfossi, Isabella Russo, Katia Bonomo, Mariella Trovati (UKPDS) The cardiovascular effects of metformin: further reasons to consider an old drug as a cornerstone in the therapy of type 2 diabetes mellitus. Current Vascular Pharmacology. 2010 May;8(3):327-37. Review. PMID: 19485923. Available Online.

C Lamanna, M Monami, N Marchionni, and E Mannucci. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes, Obesity, Metabolism. 2011 Mar;13(3):221-8. doi: 10.1111/j.1463-1326.2010.01349.x. PMID: 21205121. Available Online.

Hannah J. Whittington, Andrew R. Hall, Catarina P. McLaughlin, Derek J. Hausenloy, Derek M. Yellon, Mihaela M. Mocanu. Chronic metformin associated cardioprotection against infarction: not just a glucose lowering phenomenon. Cardiovascular Drugs and Therapy. February 2013, Volume 27, Issue 1, pp 5–16. Available Online.

J. A. Johnson, S. H. Simpson, E. L. Toth, S. R. Majumdar. Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with Type 2 diabetes. Diabetes Med. 2005 Apr;22(4):497-502. PMID: 15787679. Available Online.

Christianne L. Roumie, MD, MPH; Adriana M. Hung, MD, MPH; Robert A. Greevy, PhD; Carlos G. Grijalva, MD, MPH; Xulei Liu, MD, MS; Harvey J. Murff, MD, MPH; Tom A. Elasy, MD, MPH; Marie R. Griffin, MD, MPH. Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort study. Annals of Internal Medicine. 2012 Nov 6;157(9):601-10. doi: 10.7326/0003-4819-157-9-201211060-00003. PMID: 23128859. Available Online.

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Sara Gandini, Matteo Puntoni, Brandy M Heckman-Stoddard, Barbara K Dunn, Leslie Ford, Andrea DeCensi, and Eva Szabo. Metformin and Cancer Risk and Mortality: A Systematic Review and Meta-Analysis taking into account Biases and Confounders. Cancer Prevention Research (Philadelphia). September 2014; 7(9): 867–885. doi:  10.1158/1940-6207.CAPR-13-0424, Available Online.

Disclaimer

1) Diagnosis, Advice, and Treatment:  This article is intended for educational and informational purposes only and is not a substitute for professional medical advice. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. Do not start or stop taking any medication based on what you have read in this article. Consult a licensed physician for the diagnosis and treatment of any and all medical conditions. Dial 911 – or the equivalent emergency hotline number – for all medical emergencies. Consult a licensed physician before changing your diet, supplement or exercise programs.  2) Photos, External Links & Endorsements: This article is not intended to endorse companies, organizations or products. Links to external websites, depiction or mention of company names or brands, are intended for illustration only and do not constitute endorsements.

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