Unfortunately, there is a widespread belief that all man-made prescription drugs have adverse side effects and that natural substances don’t. Moreover, many such substances are available without a prescription as dietary supplements. This can cause problems. For example, metformin (Glucophage®) is the first line treatment for type-2 diabetes, or T2D. Metformin is also quite useful in preventing T2D in people who are pre-diabetic. It reduces the amount of glucose that is released from the liver and increases the transport of glucose into muscles, increasing insulin sensitivity and decreasing glucose absorption from the gastrointestinal tract. Metformin may also be useful in treating other diseases, and possibly even slowing down aging. It reduces the incidence of cancer and mortality, while helping people retain proper cognitive function. It may also affect aging by activating AMP-activated protein kinase (AMPK) and reducing DNA damage. So, metformin favorably influences metabolic and cellular processes that are closely linked to the development of age-related problems, such as inflammation and cellular senescence. Since it is so inexpensive and easy to obtain, metformin could be especially useful in countries where many people don’t have much money.

Perhaps the most exciting potential use of metformin is in extending the lifespan of not just people who have diabetes, but also in slowing down the aging process. It does this by affecting several biochemical pathways that are important in how prediabetics age.

Metformin (850 mg twice daily) was administered to subjects in a Diabetes Prevention Program (DPP). It reduced the incidence of T2D by 31% compared to placebo after three years and prevented diabetes. Moreover, metformin improved risk factors for cardiovascular diseases and subclinical atherosclerosis (coronary artery calcium) in male participants. Partly due to these important health benefits of metformin, some scientists are rejecting the idea that we die of old age. Instead, we die of cumulative failures that occur within our cells and tissues. These failures are not inevitable breakdowns. They are reversible conditions of aging.

One of the most important of these failures is a less active AMPK. Its concentration is relatively high when we are young, but decreases with age. Recent studies have suggested that increasing the activity of AMPK can prevent and possibly reverse the life-shortening effects of aging. Some scientists are beginning to refer to AMPK as a suppressor of aging itself. As AMPK decreases when we age, we become less energetic and more obese, while becoming increasingly vulnerable to cancer and diseases associated with impaired DNA and protein function. As a person accumulates abdominal fat, this leads to reduced insulin sensitivity, system-wide smoldering inflammation and metabolic syndrome. This, in turn, can lead to many forms of cancer, as well as cardiovascular, neurodegenerative and autoimmune diseases (including T2D).

The modern Western lifestyle with its overabundance of nutrients and low level of physical activity exacerbates this. When a person’s caloric intake is too high and/or physical activity too low, AMPK activation decreases. As a result, cells decrease their energy-releasing ATP-generating activities and shift to energy-storing processes that generate new fat deposits and make excess new glucose. Moreover, energy inefficiency eventually leads to the dysfunctions that are often described as inevitable diseases (or symptoms) of aging. So, restoring the activity of AMPK in the elderly may not only increase longevity, but also help to fight the symptoms of aging. This hypothesis was supported by a clinical study in which subjects with T2D either received metformin (which activates AMPK) or placebo. They were compared to subjects who did not have T2D. It was found that the subjects who were diabetic and received metformin lived a median of 15% longer than did matched controls without diabetes. So, there is a clinical trial underway, called Metformin in Longevity Study (MILES) and another that is being planned called Targeting Aging with Metformin, or TAME. These studies will look at the effects of metformin on longevity.

However, there could be an important factor that could lead to a serious mistake. One way that metformin can increase the lifespan of cancer patients is by inhibiting our natural antioxidant system, called the Nrf2/ARE system. At moderate doses, many dietary antioxidants in green tea as well as many colorful fruits and vegetables can activate this system. This can prevent the accumulation of too many free radicals and reactive oxygen species (ROS). It’s also possible that the much higher doses of pure dietary antioxidants (like ECGC and resveratrol) can also prevent the accumulation of ROS. This might be able to prevent many diseases caused by smoldering inflammation (like cancer and cardiovascular diseases). However, once a patient gets cancer and starts chemo- and/or radiation therapy, such dietary supplements could become deadly. That is, cancer cells can hijack the Nrf2/ARE system to make them multidrug resistant and resistant to chemotherapy. So, the same things that prevent cancer can reduce the lifespan of patients who get cancer and start chemo- and/or radiation therapy. So, physicians and oncologists who are treating patients with chemo- and/or radiation therapy should probably warn their patients about the potential dangers of taking dietary supplements that contain high doses of pure antioxidants. Moreover, the use of such supplements should be carefully controlled in the MILES and TAME clinical trials.

Smith RE. Systems Thinking in Medicine and New Drug Discovery, Volume One. Cambridge Scholars Publishing, Newcastle upon Tyne, UK (2018).
Smith RE. Systems Thinking in Medicine and New Drug Discovery, Volume Two. Cambridge Scholars Publishing, Newcastle upon Tyne, UK (2018).