Is Metformin the Metabolic Holy Grail?

Top scientists agree that metformin is an antiaging drug …

Treatment with metformin mimics some of the benefits of calorie restriction

Metformin is an oral antidiabetic drug used for the treatment of type-2 diabetes, a metabolic disorder characterized by high blood glucose, insulin resistance, and relative insulin deficiency (even though insulin levels are higher than normal). It is also used for metabolic syndrome and glucose intolerance, prediabetic conditions.

Metformin was introduced in Europe in 1958, and Canada in 1972. However, it was not until 1995 that the FDA got around to approving it in the United States. Falsely conflating it with the drug phenformin,* the FDA deemed that metformin research and clinical experience performed and gathered outside the US was substandard. In truth, metformin is much safer than phenformin, as the data show.1

“If the same criteria were used for older people as are used for younger people, nearly every senior citizen would be diagnosed as diabetic.”

Plus, then as now, the FDA moaned that it had been “hobbled” by budgetary considerations. Compared to the National Institutes of Health’s budget ($31.3 billion requested for this fiscal year vs. $4.9 billion for the FDA), the FDA claims it doesn’t have enough to afford the regulatory work required for speedy approval.† Despite the retardation of its acceptance, metformin is now believed to be the most widely prescribed antidiabetic drug in the world and in the United States alone, more than 48 million prescriptions were filled in 2010 for its generic formulations.

* Phenformin had been withdrawn in 1976 due to the stupidity of certain doctors who continued to prescribe it in the face of abnormal liver or kidney function. See ref. #2.

† FDA Commissioner Margaret Hamburg conceded before Congress that, “the FDA is relying on 20th century regulatory science to evaluate 21st century medical products.” Von Eschenbach A. Medical Innovation: How the U.S. Can Retain Its Lead. The Wall Street Journal, February 14, 2012.

We Are All Diabetics … or Prediabetics

While it is not widely publicized, “one of the most universal changes with age is a progressive loss of glucose tolerance (Fig. 1),” writes Life Enhancement’s Dr. Ward Dean, an early champion of metformin.2 “When this loss of glucose tolerance becomes pronounced, it is diagnosed as diabetes. The diagnostic criteria for older people are much less strict than the criteria for younger people. If the same criteria were used for older people as are used for younger people, nearly every senior citizen would be diagnosed as diabetic.”2 In effect, we are all diabetics, or prediabetics. “The most likely cause of this loss of glucose tolerance with age is a progressive loss of insulin sensitivity—i.e., a loss of sensitivity to insulin by hypothalamic receptors, and a decreased response to glucose and insulin by the peripheral tissues.”2

 

In a new paper, a select group of 
scientists show that long-term 
treatment with metformin starting at 
middle age prolongs health-span 
and lifespan in male mice.

Metformin is a “Healthy Aging” Drug

Scientific literature supports the wider use of metformin. And now even “healthy aging” researchers are applauding metformin. In a new paper published in Nature Communications, a select group of scientists—many of whom are well know for their calorie restriction (CR), resveratrol, and sirtuin research—show that long-term treatment with metformin (at a mere 0.1% of diet) starting at middle age prolongs health-span and lifespan in male mice.3 In their opinion, this strongly suggests that metformin could lead to improved health-span and lifespan in humans too.

Metformin Benefits Similar to those of Calorie Restriction

In fact, the researchers show that treatment with metformin mimics some of the benefits of calorie restriction, including improved physical performance, increased insulin sensitivity, and reduced low-density lipoprotein and cholesterol levels without a lower intake of calories. They account for this by showing that metformin increases AMP-activated protein kinase activity (AMPK) and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation.

The results of this new study indicate that these metformin-driven actions may contribute to the beneficial effects of metformin on healthspan and lifespan. Taking into consideration the current literature and epidemiological data, this “raise[s] the possibility of metformin-based interventions to promote healthy aging.”

Diabetes Accelerates Aging

Along with its ability to enhance insulin sensitivity, metformin induces glycolysis‡ and suppresses gluconeo­genesis§ in the liver. Metabolic syndrome is similar to diabetes because it, too, accelerates aging, by increasing the risks of cardiovascular disease, cancer, and inflammatory disorders, all of which reduce lifespan. Because metformin treatment has been associated with reduced risk of cancer and cardiovascular disease, the possibility of a beneficial role of metformin for other age-related diseases is suggested.

‡ Glycolysis is the metabolic pathway that converts glucose, into pyruvate. The free energy released in this process is used to form the very valuable high-energy compounds ATP (adenosine triphosphate) and NADH (reduced nicotinamide adenine dinucleotide).

§ Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as pyruvate, lactate, glycerol, glucogenic amino acids, and odd-chain fatty acid. It is one of the two main mechanisms humans and many other animals use to keep blood glucose levels from dropping too low (hypoglycemia).

To date, among the pharmacological interventions that can delay aging and the incidence of age-related diseases are the use of resveratrol and rapamycin. What’s more, many of these interventions are based on the study of calorie restriction mimetics, those that reproduce physiological and anti-aging effects found in CR animals. Indeed, several studies propose that metformin’s actions resemble CR. Microarray analyses have shown that metformin induces a gene expression profile that aligns with that of CR, although conflicting results have been shown in lifespan extension studies.

Energy Balance and Glucose and Fat Metabolism

As mentioned above, metformin increases AMPK activity (AMPK is an enzyme involved in cellular and whole organism energy balance, as well as glucose and fat metabolism; it triggers an increase in intracellular energy production).

Metformin treatment is associated 
with reduced risk of cancer and 
cardiovascular disease, thus there 
might be a beneficial role of 
metformin for other age-related 
diseases.

Apart from that, evidence also suggests that metformin may also act via mechanisms independent from AMPK. Metformin may partially enhance intracellular electron transport chain activity resulting in mitochon­dri­al performance improvement. By altering energy production, metformin may lead to energy depletion thus inducing glycolysis to maintain cellular metabolism.

Plus, there is no evidence that metformin induces the generation of reactive oxygen species or accumulation of oxidative damage. There is even evidence that a important transcription factor is activated by metformin, thereby increasing expression of antioxidant genes in cell and animal models. Less oxidative damage may contribute to the inhibitory effects of metformin treatment in cancer models.

CR benefits without CR liabilities.

As Durk Pearson & Sandy Shaw have related, metformin has been found to extend lifespan in the nematode Caenorhabditis elegans in a new Cell paper4 (see “Metformin Increases Lifespan of C. elegans Via Its Effects on the C. elegans Resident Bacterium” in the August 2013 issue). They comment that the Cell researchers found that metformin extended lifespan in the nematode Caenorhabditis elegans by acting as an antibiotic that altered the metabolism of the E. coli that are the worm’s resident bacterium.

The above finding, along with conflicting results in drosophila (fruit flies) and mammals, led the Nature Communications researchers to examine the use of metformin on middle-aged male mice. These mice were given either a standard diet alone or one supplemented with a 0.1% or 1% of metformin for the remainder of their lives. The researchers found that the 0.1% diet led to healthier and longer lives in mice. Diet supplementation with 0.1% metformin led to a 5.83% extension of mean lifespan, and a distinct right-shift of the survival curve (Fig. 2).

Lessening Aging’s Harmful Effects

In summary, the current research reveals that metformin use lengthens lifespan and also lessens the harmful effects of aging in male mice. Also, metformin’s effects share some of the effects of CR, even with an increased intake of food. CR benefits without CR liabilities.

The researchers also found no evidence that long-term exposure in the mice inhibited oxidative phosphorylation, suggesting that the mice adapted to metformin. Furthermore, this adaptation “produced benefits, including reduced oxidative stress and increased antioxidant defenses, leading to lower oxidative damage accumulation and inhibition of chronic inflammation.”

Metformin’s Mechanism of Action

Dr. Dean believes that metformin is unlike other anti-diabetic drugs such as sulfonylureas (e.g., Glyburide, Diabinase, Micronase, etc). This is because, instead of trying to squeeze more insulin out of your pancreas, “it acts by increasing the sensitivity of the hypothalamus and peripheral tissues (like muscles) to the effects of insulin. In effect, it rejuvenates this response, restoring the effects of glucose and insulin to much younger physiological levels.”2

I recommend Metformin to 
all of my patients who are over 40 to 
take 500 mg of Metformin two to 
four times per day. 
— Ward Dean, M.D.

Not only does Dr. Dean use metformin for type 2 diabetics, he uses it with much success on his type 1 (insulin-dependent) diabetic patients too. “When used with insulin-dependent patients, I find that they are able to dramatically reduce their doses of insulin, and more easily maintain stable levels of blood glucose.”2 Also, he states, “One potential side effect in long-term users of Metformin, is that it may cause malabsorption of vitamin B12. Consequently, I recommend that anyone taking Metformin also supplement their diet liberally with vitamin B12.” (Ref. omitted; see ref. #2.)

For Those Using Metformin, Good News

Durk Pearson & Sandy Shaw tell us that better results may be achieved when metformin is combined with the prebiotic oligofructose than when either is used alone in the treatment of obesity (see “For Those Using Metformin, Good News”in the August 2013 issue of Life Enhancement). A defect in glucagon-like peptide 1 (GLP-1) secretion, a hormone that increases insulin secretion and induces satiety, is believed to be one of the causes of obesity. It is known that overeating blunts the GLP-1 response to food ingestion, whereas prebiotics can improve the response to the hormone.

Both oligofructose (a form of the prebiotic inulin[not to be confused with insulin]) and metformin are known to improve GLP-1 sensitivity. In a new study,1 researchers decided to test whether a combination of these two treatments would result in a greater improvement in obese rats on a high fat high sucrose diet as compared to the result of treatment by metformin or oligofructose alone, and they found that the two were better together (Fig. 3).

The researchers observed a decrease in energy intake, percent body fat, and blood glucose with both oligofructose and metformin. The combination resulted in improvement as compared to the individual treatments.

“The interaction between OFS [oligofructose] and MET [metformin] affected fat mass, hepatic TG [liver triglycerides], secretion of glucose-dependent insulinotropic polypeptide (GIP) [a satiation hormone] and leptin, and AMPKalpha2mRNA and phosphorylated acetyl CoA carboxylase levels. The rats in the OFS group had lower fat mass than the control rats, and rats in the MET group and the OFS+MET group had lower fat mass than those in the control and OFS groups. Thus, MET or the combination of OFS + MET resulted in a superior outcome by reducing fat mass as compared to that of OFS alone, while OFS alone reduced fat mass as compared to controls.”

In their conclusion, metformin when combined with oligofructose has “the potential to improve metabolic outcomes associated with obesity.”

According to Durk & Sandy, “This is very good news for those taking metformin for diabetes, obesity, or obesity-related metabolic defects (such as insulin resistance), assuming that the metformin-oligofructose combination works similarly in people as it did in the obese rats. (Current data imply that it does.) Simply take supplemental oligofructose (we use long chain inulin) 2 or 3 times a day along with your usual dose of metformin.”

Reference

  1. Pyra et al. Prebiotic fiber increases hepatic acetyl CoA carboxylase phosphorylation and suppresses glucose-dependent insulinotropic polypeptide secretion more effectively when used with metformin in obese rats. J Nutr. 2012;142:213-220.

Life Extension Uses of Metformin

Also according to Dr. Dean, “Diabetes is believed by many gerontologists to be an example of accelerated or premature aging. Since nearly everyone past middle age suffers from ‘subclinical’ diabetes (i.e., a loss of glucose tolerance with age, I recommend Metformin to all of my life extension patients who are over 40. I believe Metformin has a profound and truly ‘rejuvenating effect’ on glucose and insulin metabolism. Among other benefits, this results in a reduced rate of pro-aging cross-linkages in collagen. In our book, The Neuroendocrine Theory of Aging and Degenerative Disease (Dilman and Dean, 1992), we list the following benefits of Phenformin, which I believe are shared by ­Metformin:

  • Lowers blood cholesterol, triglycerides, and beta-lipoproteins.
  • Reduces development of atherosclerosis.
  • Reduces insulin levels.
  • Increases hypothalamo-pituitary sensitivity (which declines with age).
  • Improves cellular immunity.
  • Reduces incidence of chemically-induced cancer in rats.
  • Enhances activity of anti-cancer drugs.
  • Suppresses the growth of some tumors.”

And also, to increase maximum lifespan in experimental animals.

Cautions and Contraindications

Metformin should be used with caution and under the supervision of their physicians by patients with compromised liver or kidney function, or congestive heart failure.

Summary

In view of its record of safety and paucity of adverse side effects, its physiological mode of action, and its broad range of beneficial effects, I strongly encourage all of my patients over the age of 40 to take 500 mg of Metformin two to four times per day.”

References

  1. Lautatzis ME, Goulis DG, Vrontakis M. Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: A systematic review. Metabolism. 2013 Jul 22. doi:pii: S0026-0495(13)00187-X. 10.1016/j.metabol.2013.06.006. [Epub ahead of print]
  2. Dean, W. http://warddeanmd.com/metformin-an-effective-and-underappreciated-life-extension-drug/ Accessed August 20, 2013.
  3. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013 Jul 31;4:2192.
  4. Cabreiro et al. Metformin retards aging in C. elegans by altering micorbial folate and methionine metabolism. Cell. 2013;153:228-39.