Standing in a pub in the Netherlands not so long ago, I was with some old college friends, two in their thirties and the rest of us around 50 and all of us doctors. “Well”, one of the around fifties said after a few beers, “in all these years, we have not really changed, we still look about the same and we do not behave very differently either! Unlike the generation before us”.
“Yes”, someone else said, “I have always felt like 30, 35 and that is still the case”. We all agreed with that, we all felt like we had in our thirties and certainly not like fifty year olds. The two guys in their thirties agreed: “yes that’s true, you look young, have the same interests, you dress the same, and love the same music as we do …”
I looked at the undamaged faces of the youngsters and the wrinkled heads of my peers (my own, I already know!) and thought: let me not spoil the fun. The evening was still very pleasant and the younger ones were treated generously to beer.
On the way back in the plane I read an article in El Pais, coincidentally it was about the current generation of fifty year olds. That they have a lifestyle that is very similar to that of people in their thirties. They go to discos, do dangerous sports, undertake adventurous holidays and buy large motorbikes.
We used to call it mid-life crisis but the main story line was that the perception of age has clearly changed in recent decades. A person in his fifties does not feel any different to when he or she was 20 years younger, and therefore does not behave in any other way. All very beautiful, but of course this is a socio-cultural phenomenon. From a medical and biological point of view, not much has changed, a person aged 50 will still be confronted with age-related illnesses and death on average 20 years earlier than someone in their thirties. Unfortunately. We can feel and behave like someone younger, but the calendar and biology will not be fooled.
The aging process is inexorable. During life, many billions of cell divisions take place in our body, and during the course of time there are mistakes in that process. Herein lies the core of aging, false cell divisions lead to reduced cell function and to cancer for example. In the last half century, the average life expectancy in Europe has increased steadily, to stay around 79 for men, and around 83 for women. Despite medical progress and an improved lifestyle, less smoking and healthier eating, it does not seem likely that this survival will increase much in the short term. Ultimately, most mortality is the result of diseases associated with ageing: cancer, cardiovascular disease, Parkinson, Alzheimer’s disease. And if we were to solve the condition of cancer medically, then the average life expectancy will only increase by about 3 years, because if you have solved one problem, the older person will often run into the next one.
Scientific research into aging is “hot”, especially in Silicon Valley in California. Billions of “tech dollars” are being invested in futuristic projects by tycoons such as Elon Musk (founder of Tesla and Space-X), Bill Gates (philanthropist and founder of Microsoft) and the Facebook couple Zuckerberg, Ms. is a neurobiologist. On the one hand, for these people their own mortality may be unacceptable, on the other hand a major breakthrough in this area is very interesting. The hope is to eliminate diseases such as cancer and eventually push mortality further away.
At the same time, there are scientists who reason that it will take a lot of time and money before we can cure all diseases of old age, why not look for a medicine that slows down the aging process itself, so that the population stays healthier and fitter for longer? The medicine which is at the front of this hope is metformin, derived from a component of a plant, the French lily, which was used in the Middle Ages in the treatment of diabetes. Metformin as a registered medicine has been known for 60 years, and many millions of diabetics have already been treated worldwide. This does not sound very futuristic but: it is safe, the side effects are known and it is cheap, making it accessible to very many people. A trial to investigate the effect of metformin as an anti-ageing drug was approved by the FDA in 2015.
In recent years much research has been published on the effects of metformin on the ageing process. Belgian researchers found that roundworms, treated with metformin, remained fit and healthy for longer and also developed fewer wrinkles. Mice treated with metformin were found to be more active and to live significantly longer. Patients with diabetes have a shorter life expectancy because they are faced with all kinds of complications of the disease later in life. But …: diabetic patients treated with metformin nevertheless appeared to live longer than non-diabetic patients (who obviously did not take metformin).
The mechanism of action of metformin has not yet been fully clarified, but what seems to be of importance is the activation of the enzyme AMPK that reduces blood sugar by stimulating the energy use of cells. AMPK activity is crucial in all tissues of our body and decreases with age. In addition to lowering blood sugar in old age diabetes, increased AMPK activity plays an important role in the prevention of other diseases associated with aging, such as cardiovascular disease, dementia and cancer.
Metformin and cancer. Diabetics have an increased chance of developing cancer, but recently several studies have shown that different types of cancer are less common in diabetics who take metformin. There are also indications that metformin might play an additional role in the treatment of some forms of cancer.
Metformin and cardiovascular disease. Several studies show that metformin use plays a role in the prevention of cardiovascular disease by interfering with the development of arteriosclerosis at various levels. In addition, after a heart attack, metformin users had a significantly better chance of survival than non-metformin users.
Metformin and neurodegenerative disorders. Several recent animal studies have shown a possible preventive role of metformin in diseases related to degeneration of the nervous system (Parkinson, Alzheimer’s disease). In 2016, a study was conducted in patients with early stage Alzheimer’s disease which showed that the group which had taken metformin for 12 months, had improved memory instead of a deterioration.
Metformin and “all-cause mortality”. Recently (August 2017) the results were published of a study that analyzed the joint results of 53 studies on the effect of metformin. This showed that the mortality rate among metformin-using diabetes patients during the observations was significantly lower than in patients who used other medicines, but … also lower than in non-diabetics. These lower mortality rates were mainly explained by the finding that metformin users developed fewer cardiovascular diseases and less cancer.
The fact that not everything is known about the mechanism of action of metformin in aging, and the fact that people are not roundworms or mice, means we need some restraint in optimism. Metformin is a medication that can also have side effects and can have interaction with other medicines. Moreover, until now it has only been widely used in people with diabetes …
Given the positive indications, the American government decided a few years ago to approve a large-scale study into metformin as a medicine against aging (the “TAME” study, Targeting Aging with Metformin). Because metformin is a pre-existing drug, and therefore can no longer be patented, the financing of this study has been problematic to date. For Big Pharma it is not interesting because it is not profitable. Governments have withdrawn more and more and leave the development of new medicines to the pharmaceutical industry, even though an improved ageing process could be realized by many for relatively little money. And the tycoons? Our fellow human beings who own billions and billions, enough to save the planet from starvation and the climate crisis at the same time? They would rather bet their billions on a possible new discovery that would bring immortality closer. If that ever happens, it will probably become so expensive that it will only be accessible to the very rich. And that is a good thing, because studies in mice have also shown that when there are too many living together, peaceful cohabitation is at stake, which can get very serious, as there will likely be insufficient food in the bin. If we all keep hanging around on this planet, it will become very busy and unpleasant, likely leading to famines and wars. Or maybe Elon Musk can offer us all a one-way trip to Mars?