Metformin as a longevity drug

Metformin is the first line of therapy for type-2 diabetes patients, but it holds far more potential as a potential agent for preventing age-related diseases and extending health and lifespans.

The story of metformin originated with a plant-based remedy for diabetes symptoms; the plant Galega officinalis (aka. French Lilac) was given—among many other uses—to diabetics to help reduce frequent urination.

Fast forward to the early 20th century; guanidine was identified as the active principle in French Lilac, but purified and synthetic guanidine turned out to be too toxic, so biguanides (formed by bonding two guanidine molecules) were identified as a more tolerable glucose-lowering medication.

The process by which plants produce “beneficial toxins” such as guanidine in response to stress is called hormesis; in the right dose and form, these molecules elicit their benefits by introducing a stressor that promotes beneficial adaptation in the host. Following the principle that “what does not kill you makes you stronger.”

Mechanisms of potential longevity effects

Consistently, metformin’s mechanism of action relies on disrupting the energy plants of the cell known as mitochondria. mitochondria, (namely complex 1 of the respiratory chain), which in turn leads to reduced levels of ATP production. Faced with lower energy levels, the cell adapts by limiting energy consumption and increasing efficiency. One of these adaptations to lower ATP levels and accumulating AMP (the byproduct of consuming ATP in the cell) is the inhibition of glucose production by the hepatocytes (known as gluconeogenesis); this inhibition is the main pathway by which metformin lowers blood glucose levels, though other parallel mechanisms of increasing insulin sensitivity and glucose uptake in the gut and muscles are also possible, if probably less relevant.

Lower ATP levels in the cell trigger a pathway known as AMPK; this is a major signaling hub that orchestrates the response to starvation. AMPK activation inhibits all growth processes, "anabolism,” and activates the breakdown, recycling pathways, and self-repair pathways. To increase efficiency, the cell reduces its energy consumption while ensuring to selectively eliminate all faulty “organelles” by recycling them for energy and building blocks while maintaining the youthful and health parts. This process is known as autophagy, or mitophagy (as it pertains to the mitochondria) and is implicated in keeping cells and tissues youthful, in addition to preserving stem cell populations.

By artificially lowering cellular energy levels, metformin serves as a calorie restriction mimetic, the first longevity intervention to be studied, and proved to extend lifespan in all tested species.

As a bonus, metformin has also been demonstrated to reduce cancer risk in retrospective and longitudinal studies.

Intriguingly, AMPK activation is a common pathway of many proposed longevity interventions, including calorie restriction, fasting, ketogenic diets, exercise, and polyphenols.

AMPK activation also seems to underpin more of the newly identified longevity interventions, even though these interventions were originally known to activate AMPK as part of their mechanism of action.

For example, SGLT-2 inhibitors are another class of diabetes medications that have been shown to improve lifespan in the NIA Intervention Testing Program (the gold standard of testing longevity interventions in mice). Originally, they work by increasing sugar elimination in urine; however, it was shown that they also activate AMPK as a “side effect” (by promoting AICAR buildup in the blood) in mice in the context of prolonging mice's lifespan.

Sources of doubt around metformin potential to extend lifespan

In a way, ATP depletion and AMPK activation have been both the “blessing and “curse” of metformin as a potential longevity drug; the same effect that can mimic calorie restriction can also blunt the benefit of exercise in promoting muscle growth.

This "drawback," as well as its failure to induce significant lifespan extension in mice in the Intervention Testing Program (despite succeeding in other mouse studies), and the lack of conclusive evidence from clinical trials (e.g., TAME), have shed much doubt on metformin as a longevity medicine.

Recent primate and human data restore hope for metformin as a longevity drug

However, very recent research restores much of the hope and confidence around metformin’s potential as a longevity drug for humans.

A study found that metformin slowed down aging across multiple organs in cynomolgus monkeys based on novel innovative epigenetic and multiomic monkey aging clocks. Moreover, the age reversal seemed most promising for the brain, with the metformin-treated monkeys showing up to 6 years of brain aging reversal based on cognitive abilities. Also, brain and systemic oxidative stress and inflammation, both markers of aging, decreased in metformin-treated monkeys.

A recent preprint analyzed 50 clinical longevity intervention studies for their effect across 16 epigenetic biological aging clocks in humans. While most studies tend to use one or two aging clocks (algorithms) to evaluate the effect of treatments on epigenetic age, the view across 16 different clocks is perspective-changing. Some seemingly solid interventions like rapamycin (repeatedly showed significant lifespan extension in gold-standard testing in mice) as well as senolytics. Metformin, however, proved to slow down aging significantly when evaluated across the 16 aging clocks.

Conclusion

Beyond restoring confidence in metformin as a highly safe and potentially effective longevity intervention, the findings also serve as a reminder not to jump to premature conclusions based on animal models (especially mice as they are fundamentally different in basic biology, lifespan, size and lifestyle) from higher primates, as well as not over trusting any single aging clock algorithm as a single source of truth when evaluating longevity interventions.