Medieval Monks to Modern Science
As we’ve discussed previously, one of the best ways to prolong the life of the tiny worm C. elegans is to disable the worm’s version of the growth-promoting gene IGF-1. The actual name of this gene is daf-2, and it is not just a stand-in for IGF-1 – it’s also the worm’s version of the hormone insulin.
Insulin, like IGF-1, is growth-promoting, but its primary role is to regulate blood sugar. When we eat carbohydrates, enzymes in the gut break down most of the various forms into the simple sugar glucose. We absorb this glucose, and after entering the blood it is called ‘blood sugar’. Our cells use sugar from the blood as fuel, and this is where insulin comes into the picture. When our blood sugar rises after a meal, we secrete insulin from the pancreas to enable cellular uptake. You can imagine insulin as a tiny key that opens a gate in the cell, allowing sugar to enter. This mechanism helps us fuel our cells, but it is also necessary because high blood sugar levels can damage our blood vessels. This means we want to lower blood sugar when it spikes after eating, even if our cells don’t need energy at the time. We primarily do so by shuttling the sugar to fat cells, where it can be converted into fat and stored. If blood sugar levels still remain high, though, the last resort is to excrete it in our urine.
Since ancient Egyptian times, doctors have described patients with endless thirst, fatigue and a tendency to urinate a lot. For some reason, multiple people have discovered that the urine of these patients tends to taste sweet. We now know this is because the patients’ bodies are trying to lower their blood sugar. They have diabetes, known as ‘sugar sickness’ in my native Danish. In diabetes, insulin fails to lower blood sugar sufficiently, making the body desperate to get rid of it. There’s an autoimmune version, type 1 diabetes, where the immune system mistakenly kills the insulin-producing cells. But there’s also a lifestyle-dependent version called type 2 diabetes. Here, patients do produce insulin, but their cells become ever less responsive to it. The key stops being able to open the gate. This especially seems to happen to overweight people and people who eat high amounts of processed foods.
While type 2 diabetes is a disease, there are actually levels of what is called ‘insulin sensitivity’ even among healthy people. That is, different people require different amounts of insulin to remove sugar from the blood. You can imagine insulin sensitivity as a spectrum. At one end, the cells of an athlete will be insulin sensitive, requiring only a small amount of insulin to take up blood sugar. At the other end, the cells of a diabetic person will not react even at high insulin levels.
If we extrapolate from the worm C. elegans, insulin-sensitive people should live longer. After all, dampening the equivalent of insulin signalling increases the lifespan of the worms. Scientists find that human centenarians do indeed tend to be insulin sensitive and have tight blood sugar control. Similarly, the lifespan of mice can be increased by disabling insulin signalling in fat cells.
Unfortunately, insulin and blood sugar levels tend to rise with age, and so does the risk of diabetes. In the 1990s, Swedish researcher Staffan Lindeberg wondered whether it really has to be this way. Lindeberg was studying the people of Kitava, a lush tropical island belonging to Papua New Guinea. The traditional diet of the Kitavans is based on local crops, such as yams, taro, fruit and coconuts, supplemented with a little fish. This diet is sixty-nine per cent carbohydrates, or high-carb if you will. We might naively expect that to mean the Kitavans would tend to have high blood sugar and insulin levels.
Lindeberg tested this theory by collecting blood samples from average Swedes and comparing them to blood samples from the Kitavans. He found that the Kitavans had less insulin in their blood than Swedes, despite eating a more carbohydrate-rich diet. And while insulin levels rose with age among the Swedes, there was no such increase among the Kitavans. In general, the Kitavans were exceptionally healthy. Lindeberg only managed to find two overweight people on the island and both were just back home visiting after having moved to a big city on the mainland to become businessmen.
The Kitavans prove that carbohydrates per se are not the problem when it comes to insulin sensitivity. If you have a healthy weight, like the Kitavans, and your carbohydrates are whole foods, not candy, you’ll be insulin sensitive and healthy. However, realistically, most of us will not be able to eat like the Kitavans all the time. If we still want to be healthy, the optimal approach would be to measure our insulin sensitivity and blood sugar levels while experimenting with different diets or foods. We know that people can have very different-sized blood sugar spikes upon eating the same foods, from oatmeal to candy. Some of that could be due to genetics, but another reason is the gut microbiome. There is a curious correlation between specific species of gut bacteria and the size of blood-glucose spikes from different foods.
The less time-consuming and equipment-heavy approach to becoming more like the Kitavans would be to adopt some tried-and-true habits. The best one is to exercise – or just move – after eating. The muscles are the primary destination for blood sugar, and the simple act of using them can help lower blood sugar spikes substantially. Even a short walk or some bodyweight movements after a meal can be beneficial.
There are, however, also more drastic approaches to taming blood sugar, the most fascinating of which takes us to the gardens of medieval monasteries.
* * *
If you were living in the Middle Ages and began feeling symptoms of diabetes, such as unquenchable thirst, fatigue and frequent urination, you might get sent to some monk at a monastery. Upon listening to your complaints, he would go to the garden, pick up a beautiful purple shrub and grind up a preparation for you. The shrub – French lilac, or goat’s rue – is not some hocus-pocus treatment. A substance from this perennial can actually lower blood sugar and mitigate symptoms of diabetes. We still use it today, although the original substance has been further developed into a drug. This drug is called metformin and it was approved for the treatment of diabetes in 1957. Since then, it has been one of the most widely used diabetes medications worldwide.
After spending decades as an anonymous diabetes drug, metformin has suddenly burst on to the anti-ageing stage. In a now-famous study, researchers compared the lifespans of three groups: healthy people, diabetics on metformin and diabetics using other drugs. As expected, most diabetics lived shorter lives than average. Save one glaring exception: diabetics on metformin lived longer than the non-diabetic average. That is, when using metformin, these people – who are suffering from a life-shortening disease – lived longer than comparable healthy controls. Does that mean metformin is the first anti-ageing drug?
It might surprise you to learn that while we know the effects of metformin – lowered blood sugar, improved insulin sensitivity – we don’t actually know how it works, even though it was approved decades ago and is used daily by millions of people. The most widely accepted theory is that metformin activates an enzyme called AMPK which works like an energy sensor in our cells. Under normal conditions, AMPK is activated when the cell lacks energy. It switches the cell into a kind of energy-saving state, as seen when a person is fasting or on a calorie-restrictive diet. Metformin advocates argue this makes metformin like fasting in pill form.
A second theory is that metformin doesn’t actually work on us, but on our gut bacteria. Giving mice metformin improves their insulin sensitivity, but you can transfer the effect by transferring the gut bacteria. That is, by taking the gut bacteria from a metformin-treated mouse and giving it to a new mouse, the new mouse also becomes more insulin sensitive, even if it never got the drug itself.
Both effects could be right and contribute independently. It is not uncommon for drugs to work in several different places at once. Actually, our bodies are so complex that it’s nearly impossible to make a drug that won’t impact us in multiple ways. When initially designing drugs, researchers simply cross their fingers that none of these extra interactions will lead to unwanted side effects.
A third theory about metformin is that it inhibits inflammation, and this is where it runs into trouble in my opinion. Inhibiting inflammation in the body might sound like a good thing, but you have to remember that inflammation – and damage in general – is not always bad. Sure, if you have high levels of inflammation because you live on chips and soda, it may be a good idea to alleviate it. But inflammation is also a key player in hormesis. For instance, after exercise, there are heightened levels of inflammation that serve as one of the ‘damage signals’ that initiate a cascade of healthy adaptations. So by inhibiting inflammation, metformin seems to also inhibit the beneficial effects of exercise. When people who don’t usually exercise take metformin and start training, they don’t gain as much endurance or muscle mass as those who don’t take metformin and they also miss out on key cellular adaptations to exercise.
That said, several prominent researchers and technologists are convinced about the benefits of metformin and use it despite not being diabetic. This group includes people with their heads screwed on right. I still wouldn’t recommend it, because the ability to improve health through exercise should carry more weight than the result of a single study showing a slight life extension. Single studies can be wrong, due to coincidences, errors, misunderstandings, lack of coffee at the laboratory or the wrong alignment of the stars. Personally, I need more data before using a diabetes drug with potential side effects.
But fortunately, metformin advocates are serious about their beliefs and share this conviction. They are currently arranging a more rigorous study to test out metformin in healthy people. In the upcoming TAME (Targeting Ageing with Metformin) trial, thousands of Americans will be given metformin or a placebo to test whether the drug can prolong life, by how much and at what cost. Stay tuned.