When cells are exposed to mitochondria damage, a central cellular fuel gauge, the enzyme AMPK, sends an emergency alert to mitochondria instructing them to break apart into many tiny mitochondrial fragments. Interestingly, AMPK is activated by the widely used diabetes therapeutic metformin, as well as exercise and a restricted diet.

Metformin is the most widely prescribed drug for the treatment of diabetes. Although, the exact molecular mechanism of action of metformin remains partly unknown despite its use for over 60 years and more than 17,000 articles in PubMed, its main mechanism of action is widely recognized as inhibition of mitochondrial complex I, increasing the glycolytic pathway through reduction of OXPHOS. Due to lower production of mitochondrial ATP, the AMP/ATP index increases and activates AMPK which further inhibits mTOR. Used at high doses it may produce lactic acidosis due to increased lactic acid production. Phenformin is metformin’s predecessor with similar effects on lactic acid production, but is a more powerful inhibitor of the mitochondrial respiratory chain which entails an increased risk of lactic acidosis. This adverse effect led to the withdrawal of this drug from the market.

The primary target of metformin is the inhibition of mitochondrial complex I→ low ATP → high AMP/ADP (energetic stress) → activation of AMPK (an enzyme that senses low energy levels and activates numerous pathways to restore the intracellular ATP)→ increased glucose transport into cells and glucose metabolism (increased insulin sensitivity). Basically, Metformin is a kind of mitochondrial “poison” that, as a result, reduces ATP production and, thus, activates AMPK. This, of course, stimulates nutrient catabolism, lowering glucose, which lowers insulin, etc.

Cells treated with metformin become energetically inefficient, and display increased aerobic glycolysis and reduced glucose metabolism through the citric acid cycle. So, cancer cells exposed to metformin display a greater compensatory increase in aerobic glycolysis than nontransformed cells, highlighting their metabolic vulnerability.

Preasbsorptive metformin activates AMPK in gastrointestinal cells, which indirectly lowers blood glucose by reducing the amount of glucose that goes into the bloodstream.

Metformin activates AMPK in liver cells, which inhibits gluconeogenesis and the liver excretes less glucose.

Pretty smart, yes?

Metformin also activates AMPK in skeletal muscle, and we know that when AMPK is activated by ATP depletion, AMPK switches on catabolic pathways that generate ATP while switching off anabolic pathways and other ATP-consuming processes, which restores the energy balance. So it is not rocket science, that Metformin blunts the benefits of exercise by reducing mitochondrial ATP production in skeletal muscle by as much as 48%. In simple terms, Metformin abolishes the improvement in mitochondrial respiration after exercise training.

Since cardiorespiratory fitness is one of the strongest factors for survival into old age, and since it decreases with age, the effect of metformin on this factor is concerning.

A study of over 7,000 patients with Alzheimer’s disease showed that, metformin increased the risk of developing Alzheimer’s . No large clinical trials have confirmed whether metformin is beneficial in non-diabetic Alzheimer’s patients. In a cohort study that followed about 9300 patients with T2DM in Taiwan for up to 12 years, the risk for Parkinson’s disease (PD) or Alzheimer’s dementia was more than double during a 12-year period for those who took metformin vs those who did not — even after adjusting for multiple confounders. The use of metformin may be associated with an increased risk for dementia in older African Americans with diabetes. This research was presented at the 2018 Alzheimer’s Association International Conference, held July 22-26, 2018 in Chicago, Illinois.

Imagine reductions in ATP production were observed in the brain or the heart or the GI tract which leads to neurocognitive decline, psychiatric instability, neuropathy, heart rate, rhythm and blood pressure abnormalities, along with gastrointestinal distress to name but a few. Underlying all of these symptoms, and indeed, all mitochondrial dysfunction, is an overwhelming sense of fatigue and malaise.

Metformin is excreted almost entirely unchanged in urine so reduced kidney function may lead to accumulation of both metformin and lactate and therefore, a metformin-associated lactic acidosis (MALA). So it’s not a secret that, Metformin may have an adverse effect on renal function in patients with T2D and moderate CKD. Mild to moderate renal impairment is common among metformin initiators. Even, FDA recommends against starting metformin therapy in patients with estimated glomerular filtration rate (eGFR) between 30 and 45 mL/min/1.73m2

By the way, Metformin alters immune reactivity first by damaging the mitochondrial ATP factory and reducing energy production capacity and then by inhibiting the signaling cascades that would normally respond to the danger signals.

So, what gives? Is metformin healthy and anti-aging, or not?

When we contrast the reduction in glucose mediated by Metformin with the damage this medication does to the mitochondria and immune signaling, along with its ability to leach vitamin B12, block insulin sensitivity and reduce aerobic capacity, one cannot help but wonder if we are causing more harm than good.

Although metformin is not often acutely toxic, the underlying mechanisms manipulated by this drug suggest that it is likely to induce and not prevent, as is so frequently suggested, chronic illness.