Metformin – Aging and the “Miracle” drug

The drug Metformin has had a lot of buzz around it ever since it was announced that trials would be done to try and name it the world’s first anti-aging drug. Leading researchers active in the fields of Gerontology, like David Sinclair, have publicly said that they’re taking it to reverse the aging process in their bodies. However, it is important to look past the hype. What is the scientific process behind drug testing? Why is Metformin being tested? And why is it always important to look at the evidence instead of the excitement?

The process of approving drugs

Drugs must be approved before they can be prescribed to patients. In the US, the body that approves drugs is the FDA (the Food & Drug Administration) whilst in Europe it’s the EMA (the European Medical Agency). EMA works closely with the national medical agencies of every EU membership state. Clinical trials are part of this approval process and take place so that we can scientifically work out if a medicine is safe and effective.

Clinical trials are the final parts of the drug discovery process. It goes from initial chemical development of the drug through testing how the drug reacts in a petri dish followed by studies in animal models. This means that by the time a clinical trial occurs, a lot of information is already known about the drug in question. The final stage to test the efficiency and safety of the drug in humans is done by performing clinical trials. To be as safe as possible, human clinical trials are designed to occur in different phases.

The 3 phases of human clinical trials

1. The first phase tests the drugs in a small group of healthy human volunteers. The emphasis at this stage is safety which is why the subjects are given a very low dose at first. This so that if any side effects occur, they are as minor as possible. Once the eventual side effects at a low dose have been found, the dosage is then gradually increased. The initial stages of drug testing will have given the scientists an idea of what dosage of the drug is likely to be effective and what the maximum dose of the drug is before it becomes toxic i.e., the maximal tolerable dose.
2. In the second stage the drug is used to treat a larger group of people (perhaps 100-300) who are ill with the disease that the drug is designed to treat. This stage checks how the drug affects people who are not completely healthy. The emphasis of this stage is to measure the effectiveness and short-term safety of the drug.
3. The third stage tests the drug on at least 500 people, and up to a few thousand patients. It is most often a double-blind clinical study that compares the drug as a treatment option against the standard treatment of the disease or against a placebo. This is done to demonstrate the true effectiveness of the drug, and to measure the safety in a larger group of people, where there are likely to be a wider range of populations with more genetic and individual differences between them.

The above summary represents the standard pathway for a brand-new drug. However, there are lots of situations where a clinical trial might need to take place, despite already being approved for use in some areas. An example of this is the drug Metformin.

Metformin – the world’s first anti-aging drug?

Metformin has been used as a drug to treat type 2 Diabetes for nearly 60 years (1). Although the exact pharmacodynamic mechanisms are not fully understood, Metformin works in general by stopping the body from absorbing more glucose from the food that we eat, whilst also increasing the glucose uptake to the cells (2). This improves insulin sensitivity – an insensitivity to insulin is a hallmark of diabetes (2).

However, in recent years investigations on Metformin as a potential drug to slow down the aging process have started to take place. This since there are possible synergies with how Metformin acts on diabetes symptoms that could also have a positive effect on some of the hallmarks of aging, such as nutrient sensitivity (3). It is gaining much attention because it is an incredibly cheap drug that could be available to a widespread population, if approved for that indication (4).

Off-label usage of drugs

In 2021 The World Health Organisation partially recognised aging as a cause of disease, which is the first step in aging being recognised as an “indication” (5). An indication is the disease or condition that a drug is intended for. When the medication is used for other indications than the approved ones, it is called “off-label usage”.

There are some medical situations where this is acceptable, but it can lead to dangerous unintended consequences. For example, the Thalidomide tragedy occurred when a drug that was originally used as a sleeping pill started to be recommended as a morning sickness pill for pregnant women, leading to severe birth defects.

Targeting aging with Metformin

Metformin is currently approved as a diabetes treatment option in diabetic patients because it has an affect on the glucose levels of the body. However, it is not approved to treat aging, and it must be investigated whether Metformin can be regularly and safely used by non-diabetics. The clinical trial that will look into this is called the TAME trial, or the Targeting Aging with Metformin trial. The TAME trial will specifically look at using Metformin to holistically treat age-related comorbidities (diseases that occur at the same time as aging) like cardiovascular disease and cancer (6).

Metformin must treat age-related comorbidities instead of aging itself to be allowed by the FDA. However, according to the Principal Investigator of the TAME trial, Nir Barzilai, it doesn’t matter what they call it – if the drug can increase the number of healthy years in people’s lives, then it will have reached its potential (7).

Extending health span – not lifespan?

However, the path ahead isn’t straight forward. Whilst most of the evidence has suggested that Metformin can extend the health span in an individual, it hasn’t yet been shown that it can extend an individual’s lifespan. In addition, there is research that suggests it might not be healthy to give it to older people.

It was found that when Metformin was administered to older animals it exacerbated the age-related dysfunction of the mitochondria (the powerhouses of the cell) and led to an increase in respiratory failure (8). This does not necessarily mean that the same thing will happen to humans, but it is an important reminder that Metformin’s ability to treat diabetes does not mean that it is guaranteed to treat aging with the same capacity.

 

References

1. Bailey CJ. Metformin: historical overview. Diabetologia. 2017 Sep;60(9):1566–76.
2. Rojas LBA, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013 Feb 15;5(1):6.
3. Kulkarni AS, Gubbi S, Barzilai N. Benefits of Metformin in Attenuating the Hallmarks of Aging. Cell Metab. 2020 Jul 7;32(1):15–30.
4. John M. Eisenberg Center for Clinical Decisions, Communications Science. [Table], Average Wholesale Prices for Diabetes Medicines. Agency for Healthcare Research and Quality (US); 2011.
5. ICD-11 for Mortality and Morbidity Statistics [Internet]. 2021 [cited 2022 Jan 26]. Available from: https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f459275392
6. TAME – Targeting Aging with Metformin [Internet]. American Federation for Aging Research. [cited 2022 Jan 26]. Available from: https://www.afar.org/tame-trial
7. Hall S. Feature: The man who wants to beat back aging. Science [Internet]. 2015 Sep 16; Available from: https://www.science.org/do/10.1126/science.aad1764/abs/
8. Espada L, Dakhovnik A, Chaudhari P, Martirosyan A, Miek L, Poliezhaieva T, et al. Loss of metabolic plasticity underlies Metformin toxicity in aged Caenorhabditis elegans. Nat Metab. 2020 Nov;2(11):1316–31.