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Metformin, a drug taken by many diabetics, has the potential to control blood sugar, as well as to prolong longevity. It may influence fundamental factors that underlie many age-related conditions including cancer, heart disease and Alzheimer’s, and play a key role in the biologic interference of aging.

What exactly is Metformin?

Metformin originates from the French lilac, a plant used in folk medicine for several centuries. It is a drug that is the first line treatment for people with Type 2 Diabetes, or pre-diabetic conditions. Metformin has been extensively studied, both with respect to the impacts of its use, and also the molecular mechanisms of its operations.

Purple French Lilac, where Metformin originates from.

The Research so far.

Data from several preclinical trials has shown early signs that the use of metformin can battle many of the risk factors associated with the aforementioned diseases. Some of these studies have shown a possible 24-36% reduction in all cause mortality, and a 40-57% reduction in cancer mortality.

Researchers have been looking at the potential of metformin for about 15 years. This research includes positive results in animal and human studies. In one often-quoted study, diabetic patients taking metformin lived longer than those who did not, including those without diabetes.

As age is a risk factor for many disabling conditions, metformin could essentially increase the period without disease, increase a person’s health span, and boost longevity.

The TAME study

With the promising data gathered from previous clinical trials, the American Federation of Aging Research (AFAR) is now sponsoring a clinical trial to analyze the impact of consuming metformin on aging, TAME (Targeting Aging With Metformin). A number of prominent aging researchers are backing the trial, and it has received widespread mainstream media publicity.
The TAME study will seek to follow two populations: one of 1,500 people who will receive metformin, and an equal size control population who will receive a placebo. The trial will look at whether metformin delays the onset of aging related diseases or disease precursor conditions such as cancer, cardiovascular diseases, and Alzheimer’s disease. This study will include people 70 to 80 years old in locations across the U.S. They will be followed for five to seven years. After this period, and once data has been presented, AFAR will request approval from the FDA to open the door to classifying aging as an indicator (disease), as well as to the development of new drugs that will target this disease of aging.

NOTE: the TAME trial has been approved by the FDA, however, the trial has yet to be completely funded. Once the TAME study is funded, and the results have been quantified and analyzed, we should have trustworthy statistics demonstrating the short term and long term impacts of metformin on average, healthy individuals.

How does Metformin work for Aging?

Metformin enters the cell by active transport systems. Once inside the cell, it migrates into the mitochondria where it inhibits ATP (energy) synthesis. As a result, the cell thinks it is in “energy bankruptcy”, effectively activating all of the calorie restriction pathways. When the calorie restriction pathway is activated, it leads to ATP energy synthesis blockage, and AMPK activation. AMPK is the enzyme that activates when we exercise. ATP depletion, and the increase in AMP levels, drives AMPK to improve insulin receptors on the cell surface, which in turn improves glucose transport, and reduces the synthesis of fatty acids. This in turn improves insulin sensitivity.

Metformin Diagram on How It Interacts with a Cell, Ultimately Increasing Insulin Sensitivity

The increase in AMPK also inhibits glucagon (hormone) signaling, which decreases new glucose from being made. The increase in insulin sensitivity and decreased glucose uptake, decreases oxidative stress and bodily inflammation, thereby leading to a decrease in all cause mortality inflammatory conditions (diabetes, heart disease and Alzheimer’s). This systemic decrease in inflammation could possibly lead to an increase in longevity.

Cancer, too?

The previous however, does not explain the additional molecular mechanisms of metformin on cancer chemoprevention pathways. There are four major mechanisms which may serve to explain metformin’s role in the possible reduction of cancer risk:

Metformin's Interactions Throughout the Body
  • Metformin can cause an increase in miRNA Let7A, and a decrease in miRNA-181, which can lead to the reduction of “dedifferentiation” terminally differentiated cells into pluripotent cancer stem cells.
  • Metformin plays a role in the inhibition of the STAT3 pathway, which is involved with apoptosis (programmed cell death) and cellular senescence (inhibition of cell division).
  • Metformin promotes activation of REDD1 which decreases protein synthesis.
  • Metformin activates LKB1, which then activates AMPK and inhibits mTOR. This results in decreased protein synthesis and increased autophagy (cell disassembly). LKB1 also increases cell polarity, cell differentiation, and reduces cell proliferation and metabolism.

All of these mechanisms may play a role in the dramatic reduction in cancer risk seen with the use of metformin.

What are the potential risks of using Metformin?

Some studies have shown a possible decrease in the absorption of Vitamin B12 in the small intestine, as well as a decrease in testosterone in women with PCOS (Polycystic Ovarian Syndrome). Metformin has the potential to precipitate lactic acidosis in those with preexisting renal insufficiency (chronic kidney disease).

Conclusion

For more than 60 years Metformin has been a powerful weapon in the fight against diabetes. But research is now showing us that it may also be an effective ally in the fight against aging.

More studies will have to be conducted before it can be used as anti aging drug, but Metformin is already being used off-label by well informed practitioners and patients for the purposes of life extension.

Joe Franceschi PA-C

Author Joe Franceschi PA-C

Joe earned his physician assistant degree at Stanford University and completed his training at the Stanford Medical Center Veterans Administration Palo Alto. With 23 years in medicine serving as a Marine Corps Naval Combat corpsman, firefighter paramedic, and Yosemite search and rescue paramedic, Joe has worked on the front lines alongside medical professionals and athletes while training those whose lives depended on the finest medical treatment available. Joe is fueled by his desire to optimize performance health and longevity which has driven these lifelong endeavors.

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