Metformin is one of the most popular, off-label, anti-aging prescription drugs. There are other drugs that show promise to extend lifespan, like rapamycin or selegiline, but metformin is arguably the most well-known, and the most common prescription drug that life-extension enthusiasts take in an effort to slow down aging and extend lifespan.
Metformin is a prescription drug that has been used for decades to treat type 2 diabetes. It’s mechanism of action is different from most diabetes drugs, given it improves insulin sensitivity (or reduces insulin resistance).
The older we get, the more insulin resistant our tissues become.
The more insulin resistant you are, the less well your tissues can process sugars. The sugar is not taken up well into cells, and lingers around in the body, causing damage. For example, the sugar creates crosslinks, which contribute to aging.
When one eats unhealthily and/or is overweight (like many people with type 2 diabetes), this process is accelerated.
Elsewhere on our blog, we provide many tips to reduce insulin resistance. Metformin is one of those ways to improve insulin sensitivity.
Metformin and longevity
However, the jury is still out whether metformin can extend lifespan in humans. That is why, for example, the TAME trial (Targeting Aging with Metformin) has been set up. It will try to find out if metformin can slow down aging and reduce the risk of various aging-related diseases.
Nonetheless, metformin is a promising drug to slow down aging.
In humans, researchers found that diabetics who take metformin in fact live longer than healthy persons who don’t take metformin (R). This is interesting, given people with diabetes live shorter lives on average than healthy, non-diabetics.
However, there are also some issues to keep in mind when taking metformin, including unfavorable “unknowns” and side effects.
Let’s start with the unknowns.
Questions about metformin
- Some studies showed that metformin could actually undo some of the beneficial effects of exercise (R,R,R).
- Metformin works as a strong mitochondrial “toxin” or inhibitor, stressing the mitochondria. A bit of stress can be good given it upregulates defense and repair mechanisms in the mitochondria – this process is called “mitohormesis” (R). But when does “a bit” of stress become too much stress? A study showed that metformin treatment late in life could actually shorten lifespan (R). It could be that in very old people (of which the mitochondria are already significantly damaged or stressed), or that in middle-aged people who exercise (which also stresses the mitochondria, accounting for many of the health benefits of exercise) and also take metformin, that the metformin taxes the already stressed mitochondria too much. That is why, for example, Harvard Professor and aging expert David Sinclair does not take metformin on days he exercises.
- Metformin mainly improves mitochondrial health or metabolism in general. However, we age because of many other mechanisms, like epigenetic alterations, protein accumulation, telomere shortening, DNA damage, and so on. These aging mechanisms also need to be addressed, via other molecules than metformin.
- Metformin works greatly in diabetics, but it remains to be seen if metformin also brings about health or longevity benefits in healthy, non-diabetic people.
Side effects of metformin
Metformin can also have side effects, such as:
- Metformin can reduce the body’s uptake of vitamin B12 (R). Therefore, it is advised to take vitamin B12 (and ideally a B vitamin complex containing all B vitamins) when taking metformin.
- Abdominal discomfort, like diarrhea, flatulence (gas), abdominal pain, nausea (R). Often, the gastrointestinal discomfort subsides after a few weeks.
- Classically, metformin intake was associated with the risk of lactic acidosis (acidification of the body) when one takes very high doses, but more recent studies have refuted this (R).
How does metformin work?
Scientists are unraveling how metformin works. Currently, it is believed that metformin works by:
- Increasing AMPK levels. AMPK is a protein that has many healthy effects on metabolism, inflammation and aging in general.
- Inhibiting important proteins in the mitochondria. This leads to more mitochondria being created, and the mitochondria protecting/repairing themselves better.
- Metformin could also alter the gut microbiome (the bacteria in our gut), which could be responsible for some of the health benefits.
- Metformin also influences other pathways, like the metabolically important PPAR-alpha receptors.
Better alternatives to metformin?
There are alternatives to metformin to extend lifespan, that not only have fewer side effects, but also impact all 12 causes of aging (rather than just mitochondrial dysfunction) and are natural, so don’t require a prescription.
In fact, there are various interesting substances that can extend lifespan while also exhibiting similar effects as metformin.
Just like metformin has been derived from natural compounds found in the French lilac flower (also called goat’s rue), various natural ingredients can have similar healthy effects on metabolism, insulin sensitivity and aging in general.
And these effects are magnified when they are combined, achieving additional, synergistic effects.
For example, fisetin can also improve metabolism. Fisetin is a natural ingredient found in strawberries for example. Fisetin has been shown to reduce or prevent insulin resistance (and inflammation) (R,R,R,R). It can also improve mitochondrial health.
Glucosamine is another substance that can improve mitochondrial health and metabolism. Glucosamine is mostly known as a supplement to improve cartilage health. However, large studies found that healthy people taking glucosamine have increased lifespans (R,R). This is even better than current metformin studies showing that diabetic patients live longer when taking metformin, an effect that still has not been described in healthy, non-diabetic people.
Like metformin, glucosamine slightly inhibits mitochondrial functioning, and induces a hormetic effect (moderate stress, leading to a better outcome; exercise is a great example). As a response to this inhibition, more mitochondria are created (in a process called mitochondrial biogenesis). Glucosamine can also increase the production of AMPK, like metformin (R,R).
Generally, and similarly to metformin, substances like fisetin and glucosamine stimulate mitohormesis, meaning these compounds impede mitochondrial functioning, making the mitochondria work better or increase their numbers. This can lead to various health and lifespan effects, including improved insulin sensitivity.
Just like metformin, pterostilbene can also activate AMPK (R). In fact, pterostilbene activated AMPK already at levels of 50 micromolar, while metformin achieved the effect at a higher dose of 2 millimolar (R).
4. How about berberine?
Berberine is sometimes mentioned as a supplement that could improve insulin resistance.
Like metformin, berberine can also activate AMPK. However, berberine is an alkaloid, which often are quite toxic compounds.
In our opinion, there are not enough studies showing that long-term berberine intake is safe, or even better, that berberine can extend lifespan in different organisms.
Metformin is not the ultimate anti-aging drug
To slow down aging, it is important to go beyond the effects of metformin, by addressing all 12 causes of aging. That’s where other natural ingredients, like alpha ketoglutarate, malate, lithium, ginger, NMN and others play a role.
Metformin is a very popular anti-aging drug. However, various natural ingredients exist that can have similar effects on mitochondrial health, metabolism and insulin sensitivity — and others that go well beyond what metformin is capable of.
Many people automatically assume metformin is better than a natural supplement, erroneously believing that pharmaceutical drugs must be stronger.
However, many of the most powerful and successful drugs are actually derived from nature, as we explain in this article.
Not to mention, the financial interests and marketing behind patentable prescription drugs, which has had a significant impact on the medical establishment’s recommendations and public opinion.
While a lot of attention is given to metformin, we should look beyond it in order to impact all mechanisms of aging in a synergistic way. By doing so, we will make the most significant impact on people’s health spans and lifespans.