63 years old but younger than ever: METFORMIN

Written by Nicolas Wiernsperger, PhD

REMEDES, Lyon, France

The leading oral antidiabetic biguanide metformin is likely the most pleiotropic drug presently known. Decades after its launching in 1957 this compound experiences a spectacular “renaissance” with over 2200 publications in 2018, suggesting a vast array of new therapeutic applications.

The actual trend toward drug repurposings applies particularly well to metformin. Notably metformin is increasingly suggested to be a very interesting anti-aging molecule. Indeed numerous publications report its experimental and clinical benefits on age-related diseases including cognitive dysfunction, early Alzheimer disease (possibly also Huntingon and Parkinson disease) and increasing lifespan.

What may appear as a big surprise is not really one if we consider multiple mechanisms of action of metformin on metabolic and vascular aspects of these pathologies.

Aging is notably characterized by increasing insulin resistance in many tissues. Metformin is known as a reference compound against this defect, either directly (glucose transport, insulin receptor signaling) or indirectly by its action on factors causing insulin resistance.

Thus recent research clearly shows its beneficial effects on oxidative stress and inflammation factors such as cytokines as well as correction of intestinal microbiota (ex: restoration of leaky gut by increasing the key Akkermansia bacteria).

These causative mechanisms are the basis of metabolic disturbances in fat, liver and skeletal muscle leading to metabolic syndrome/type2 diabetes. However also the aging brain suffers insulin resistance and this discovery has recently led to the concept of Alzheimer disease as “type 3 diabetes”.

Numerous studies show slowing down and improvement of symptoms of neurodegenerative diseases under metformin. Finally most studies confirm an old observation showing increased longevity on metformin treatment.

Mechanisms responsible for this highly promising new drug application start to be identified. It is clear that metformin mimicks caloric restriction (or intermittent fasting) leading to activation of AMPK enzyme, inhibition of mTOR and autophagy.

All diseases linked to chronic inflammation and oxidative stress are also accompanied by defects in nutritive (microvascular) perfusion, notably because vascular insulin resistance is induced by circulating inflammatory factors. Metformin has unique properties on microvascular (arteriolar) physiology allowing reestablishment of nutritive blood supply and elimination of waste products.

Aging is characterized by high prevalence of metabolic syndrome and cognitive complaints (up to 40% of population).

It is therefore not surprising that on the basis of accumulating evidences of its interest as an anti-aging compound, illustrated by the FDA-supported TAME trial which started end of 2019 in USA. It is the purpose of this conference to give a highly actualized review of these new data and concepts.