Metformin Life Extension: What We Really Know About the Drug and Aging

Metformin is a well-known, long-standing drug widely used to treat type 2 diabetes.
In recent years, research examining an additional potential of metformin has gained momentum: a possible effect on the aging process. It is important to clarify upfront that this is an active and unresolved area of research, and the use of metformin to extend lifespan in people without diabetes is currently unproven.

History of Metformin:

Metformin was first developed in the 1920s and has been used to treat type 2 diabetes since 1957.
The drug is relatively effective and inexpensive, and is considered an accepted first-line treatment for type 2 diabetes.

Metformin and Aging:

There is a known link between high chronic blood glucose levels and processes related to aging.
Metformin lowers glucose levels, leading to the hypothesis that it may also affect biological pathways related to aging. As of now, this hypothesis is being tested but has not yet been proven in healthy humans.

Mechanisms of Action (at the Research and Preclinical Level):

Metformin affects several biological mechanisms related to aging. Data on these mechanisms are primarily based on laboratory and preclinical studies, so they should be read as a possible explanation rather than proof of slowing aging in humans:

• Effect on AMPK: AMPK is a protein sometimes called the cell's "energy-saving switch." It is involved in regulating many processes such as metabolism, DNA repair, and protection against oxidative stress. Metformin activates AMPK, and this is one of the key mechanisms being studied in the context of aging.
• Effect on Autophagy: Autophagy is a process where the cell cleans itself of damaged components. Preclinical studies suggest that activating AMPK may promote autophagy, a process considered important for cell health.
• Effect on mTOR: mTOR is a protein that promotes cell and tissue growth, and its inhibition has been linked in studies to slowing aging processes in animal models. Metformin may indirectly inhibit mTOR, but its relevance to longevity in humans is still unclear.
• Possible Effect on Inflammation: Chronic inflammation is a risk factor for many age-related diseases. Some studies suggest that metformin may affect inflammatory markers, but this is an area still under investigation.

What Do Human Studies Say?

It is important to distinguish between observational studies and controlled clinical trials. Some observational studies have found an association between metformin use in diabetic patients and relatively better health outcomes, and one widely cited quote comes from a study by Bannister and colleagues (Diabetes, Obesity and Metabolism, 2014). That study compared diabetic patients taking metformin to a control group of people without diabetes, and it was not a long-term controlled trial examining mortality in healthy individuals.

It is important to know that these results are controversial. A later work (a retrospective cohort study published in 2022) re-examined the claim of a "survival advantage" and found that metformin did not improve survival in diabetic patients compared to matched non-diabetic individuals. That is, the observational associations are limited, influenced by confounding factors, and do not constitute proof that metformin extends life.

The trial expected to settle this question in people without diabetes is the TAME trial (Targeting Aging with Metformin), led by Prof. Nir Barzilai. This trial has not yet been completed (and as of this writing, has not even been fully funded), so there is still no evidence-based answer to whether metformin extends lifespan in healthy humans.

Other Effects Being Studied:

• Cardiovascular Disease: In diabetic patients, metformin is considered an accepted first-line treatment, and some studies indicate beneficial metabolic effects. The implications for people without diabetes are less clear.
• Cancer: Observational studies suggest a possible link between metformin use and a lower incidence of certain cancers, but this is an observational and unproven association, and the topic is still being researched.
• Brain Function: There are preliminary studies examining a possible effect of metformin on cognitive function, but the findings are inconclusive.

Dosage:

The dosage of metformin is determined by a doctor and varies based on age, health status, and the body's response. Typically, treatment starts with a low dose and is gradually increased. Do not take metformin without a prescription and medical guidance.

Side Effects and Risks:

Metformin should not be described as a risk-free drug. The most common side effects are digestive issues, such as nausea and diarrhea, which usually resolve over time and with dose adjustment. Alongside these, there are risks that are important to recognize:

• Lactic Acidosis: A rare but serious and life-threatening side effect, more common in people with kidney failure, heart failure, or liver problems. This is why kidney function is checked before and during treatment.
• Vitamin B12 Deficiency: Long-term use of metformin has been linked to decreased vitamin B12 levels, which can cause fatigue, nerve damage, and anemia. Therefore, it is recommended to monitor vitamin levels through periodic tests.

Is Metformin Suitable for Everyone?

Metformin is not suitable for everyone.
People with severe kidney problems or heart failure should not take the drug. Additionally, pregnant or breastfeeding women should consult a doctor before taking metformin.

In Summary:

Metformin is a long-standing, inexpensive, and effective drug for treating type 2 diabetes, and it is also one of the most intriguing drugs in the field of aging research. However, its effect on lifespan in healthy humans is still unproven: the observational evidence is limited and controversial, and the trial expected to settle the matter (TAME) has not yet been completed. Any use of metformin should only be done on a doctor's recommendation and under medical supervision, with awareness of the side effects and risks. This article is general information and does not constitute medical advice or a recommendation to take the drug.

References:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772077
https://pubmed.ncbi.nlm.nih.gov/25041462/
https://pubmed.ncbi.nlm.nih.gov/36287641/
https://www.afar.org/tame-trial
https://fortune.com/well/2023/05/04/metformin-anti-aging-longevity-risks-side-effects/