What Doesn’t Kill You . . .
Take the subway in my hometown of Copenhagen and you’ll probably see some ad for a new smoothie absolutely packed with antioxidants. The same goes for sketchy diet supplements sold by ‘influencers’ and other online pyramid schemes. However, the love story between antioxidants and health supplements actually began under somewhat more serious circumstances.
In the 1950s – a few years after the first nuclear bombs were dropped in Japan – scientists were understandably concerned about the effects of radioactivity on the human body. As always, mice had to suffer so that humans won’t. Scientists found that exposing mice to high, but not lethal, levels of radioactive radiation, accelerated the ageing process. When irradiated, the mice would develop age-related diseases sooner than normal, and they would also die earlier.
One reason radioactivity harms mice is that it creates something called free radicals in cells. These are highly reactive molecules that will damage other molecules when bumping into them. You can imagine free radicals as a bull in a china shop. When the cells of any animal are exposed to radioactivity, the bull goes on a rampage inside the cells. Scientists call the total damage done by the bull ‘oxidative stress’. So mice that are exposed to radiation have ‘high oxidative stress’.
This is where antioxidants come into the picture. The ‘anti’ refers to the ability to neutralise free radicals and you can think of antioxidants as a sedative to our bull. Because of this, the radiation researchers discovered that they could use antioxidants to protect their mice from the harmful effects of radioactivity. And their conclusion was that antioxidants help irradiated animals live longer.
The interesting thing is, though, that free radicals don’t just arise in cells that are irradiated. They’re actually produced as a normal by-product of metabolism in all of us. This means your cells are constantly at the mercy of the rampaging bull. Scientists knew this and started speculating. What if free radicals are not just the cause of radiation-induced ageing? What if they are the cause of normal ageing as well? This theory is called the ‘free radical theory of ageing’.
Simply put, the theory posits there is a sort of Faustian bargain in our metabolism: it is what keeps us alive, but it’s also what ensures that we age and die because it produces free radicals.
The theory fits the fact that free radicals are obviously causing damage, that old people have higher levels of oxidative stress than young people, and that excess oxidative stress has been linked to all age-related diseases. But fortunately, the theory also comes with an easy solution: use antioxidants to tame the rampaging bull.
This idea is many decades old now, and it has been thoroughly tested in clinical trials.
In fact, it’s been tested so much that researchers can do what is known as a meta-analysis: a huge study that analyses the data from several separate studies as one.
In one such meta-analysis – composed of sixty-eight studies and 230,000 subjects – researchers investigated whether dietary supplements with antioxidants help people live longer.
Their conclusion: people who take antioxidant supplements die earlier. They aren’t protected against age-related diseases either. In fact, it looks like antioxidant supplements will promote the growth and spread of certain cancers rather than limit them.
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In the fall of 1991, eight scientists were locked inside a huge futuristic greenhouse in Oracle, Arizona. Biosphere 2, as the building is called, was to be their home for the next two years. Their mission: to provide themselves with food, water, oxygen and the rest of life’s necessities without any outside help.
This grand experiment was done to test whether we can create a full ecosystem from scratch. On Earth, we’re lucky to already be a part of just that: nature provides us with all of life’s necessities and, if we treat her properly, she will be able to take care of us for a long time. However, when some of us eventually leave Earth to settle other planets, we’ll need to establish new ecosystems from scratch to provide for us.
As you might know, one of the most important parts of Earth’s ecosystems is trees. Not only do trees provide oxygen, they’re also living quarters for countless species and can be used as building material if needed. For these reasons, scientists envisioned trees as a pillar of their new ecosystem and planted plenty of trees in Biosphere 2. Trees live a long time, as we’ve learned, so a few years should be no problem, right?
The trees in Biosphere 2 did get off to a good start. Because of the favourable conditions inside the giant greenhouse, they grew rapidly. But before the grand experiment was over, many of the trees were already dead. What were they missing? Not care and nurture. Quite the contrary, actually. What the trees of Biosphere 2 were missing was stress. More specifically, they were missing the stress that the wind normally subjects them to.
You see, although the wind is one of the worst enemies of a tree, it turns out trees can’t do without it. The tireless onslaught of the wind makes trees build resilience and grow strong. Remove the wind, and trees become so weak that they eventually topple under their own weight.
Think back to the story of free radicals and antioxidants. Why do people die earlier when they take antioxidant supplements? For the same reason trees die without the wind. The stressor keeps the organism strong.
This biological phenomenon – getting stronger from adversity – is called hormesis. The most relatable example in humans is exercise. You might think that the actual act of, say, going for a run is what is healthy. But think about what actually happens while you’re running. Your heart rate and blood pressure skyrocket. With every step, your muscles and bones are burdened and strained. And because exercise requires energy, your metabolism shoots up, which increases the production of free radicals. That’s right, exercise directly leads to the production of harmful molecules. However, in the long term, exercise makes you healthier. That’s because the beating serves as a message. You need to get stronger.
Ironically, some of the ‘messengers’ that start this process are free radicals. That means antioxidants interfere with the process of getting stronger and healthier from exercise. Fitness influencer sales pitches notwithstanding, antioxidants can cancel out some of the benefits you get from your workouts.
While exercise is the best-known example of hormesis, there are many more in the biological world. In fact, hormesis is a fundamental part of the story of life on Earth. You can safely count on the fact that your ancestors took hit after hit after hit, including miserable periods of hunger, back-breaking work, poisoning, fist fights and life-or-death escapes from predators. Life has always been challenging and for that reason challenges have become a necessity for us.
One of the best examples of the ubiquity of hormesis in nature comes from research into the toxic chemical element arsenic. Arsenic has been called the ‘king of poisons’ and ‘poison of kings’ because it is easy to acquire, odour- and tasteless, and can be used to kill a person. As a result, it has always been a favourite among ambitious royals and various psychopaths around the world.
In recent times, arsenic has, unfortunately, also become a contaminant of drinking water in several parts of the world, so researchers have undertaken studies to investigate how the toxin affects laboratory animals.
When researchers give high amounts of arsenic to the worm C. elegans, the poison lives up to its reputation and is a sure-fire killer. However, if the worms are instead exposed to a fixed low dose, they actually live longer than usual. At the same time, they also become more resistant to heat stress and other poisonous substances. Why? Hormesis, of course. While arsenic is poisonous, low doses function as a survivable stressor that makes the worms raise their defensive capabilities.
Other researchers have even succeeded in prolonging the life of C. elegans using a pro-oxidant. The opposite of an antioxidant, this is something that increases oxidative stress. It would be like doping our metaphorical bull in a china shop with caffeine pills and giving it a smack on the backside. In their experiment, the researchers found that they could reliably increase the lifespan of C. elegans using the pro-oxidant herbicide paraquat. However, if they also gave the worms antioxidants, then the damage was neutralised and the worms lived no longer than usual.
I know it sounds insane that the ‘king of poisons’ or a powerful herbicide can be beneficial to an organism in any way. But welcome to the world of biology.
We obviously don’t have clinical trials where humans intentionally take arsenic, herbicides or other harmful substances. But there are in fact real-world parallels that showcase hormesis in humans, too.
One example is an accident that occurred in Taiwan in the 1980s. Back then, Taiwan was in the middle of an economic boom of epic proportions. As one of the Four Asian Tigers, its capital city of Taipei saw construction like never before. And in the fervour, some steel was contaminated with the radioactive cobalt-60. This steel was later used to build over 1,700 apartments, but no one noticed until the 1990s – and by then, it was too late.
It’s estimated that about 10,000 people lived in the radioactive apartments before they were torn down. These people were exposed to daily radioactivity far above normal levels, and this was a cause for concern because radiation is known to damage DNA, which can lead to cancer. However, doctors were perplexed when examining the residents’ medical histories. It turns out the apartment residents had fewer cases of virtually all types of cancer than comparable Taiwanese people.
This phenomenon has been noted elsewhere, too. Among American shipyard workers, those who work with nuclear submarines have a lower mortality rate than workers at normal shipyards. In the general US population, those living in areas with higher-than-usual background radiation live longer than average. And among physicians, radiologists – who are exposed to ionising radiation – live longer than other doctors and have a lower risk of cancer.
Let me just make absolutely clear that I do not recommend exposing yourself to radiation or ingesting various toxins. That would be a waste of good genes. We have no idea what levels could potentially be hormetic but we do know what happens if you exceed these levels: pain and a horrible death. You see, hormesis is all about the dose. It’s healthier to challenge your body by jogging than never exercising at all. But you can also exercise too much – this is called overtraining. Similarly, trees grow stronger when exposed to the wind. But if the wind becomes too strong, it will instead knock the tree over or break it in half. We only benefit from a stressor if the resulting damage doesn’t exceed our ability to repair ourselves.
It is also important to remember that not everything that is harmful or a stressor is necessarily hormetic. You will not get smarter by banging your head against the wall or improve your lung function by smoking, for instance. The stressors we react to positively are primarily those we have evolved to resist.
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Outside of exercise, one of the best places to find hormesis is in our food. That’s not because pizzas or doughnuts are secretly healthy if you just find the right dose. No, the place to look for hormetic substances is actually in the plants we eat.
You see, like so many other living things, plants prefer to live rather than get eaten. It’s just a little harder when you can’t run away from those trying to eat you. So that leaves plants with a single option for survival – fight. Some plants do this by having intimidating thorns, iron-hard shells or stinging needles. But what most plants have in common is that they also wage chemical warfare against their enemies. And we’re on that list.
It might be easy to eat a plant-based diet today, but as a Stone Age person you really had to know what you were doing. An incredible number of plants are poisonous in one way or another. Wild almonds, for instance, contain cyanide, one of the most toxic chemicals we know of. And raw cashews contain the same toxic substance as poison ivy (which is neutralised by the time they reach the supermarket, so don’t worry).
Even the plants that aren’t toxic to us (and that we regularly eat) are often toxic to other animals. Just think of chocolate and other cocoa products, which are toxic to both cats and dogs. And most of the plants we do eat still have some fight in them. Take pineapple – have you ever had a little pain in your mouth or tongue after eating one? If you have, there’s a good reason for it: pineapples contain protein-degrading enzymes. These can be used to tenderise meat, but it’s not so pleasant when you are the meat. As soon as you eat the pineapple, its enzymes will essentially start digesting you by breaking down proteins in your mouth. We’re too big for this to be a deterrent, but it’s a hefty weapon against smaller animals.
Another good example is chilli. Chillies contain a compound called capsaicin, which is what makes your mouth burn when you eat them. When a mammal eats the chilli pepper, the seeds are crushed and capsaicin is released. This ensures the mammal won’t eat chillies again any time soon. Birds, on the other hand, swallow the seeds whole, feel fine and can spread the plant far and wide. It’s a clever evolutionary system.
The fact that plants are not just passively willing to get eaten has often been overlooked when discussing their health benefits. We have overwhelming evidence that including lots of plants in your diet is healthy. But scientists are still discussing why this is. There are, of course, numerous reasons but hormesis is certainly one. For instance, compounds called polyphenols have long been hailed as one of the prime reasons plants are healthy. It was once thought that it had to be because polyphenols help us in some way – perhaps by being antioxidants? But the truth is that many polyphenols are a little bit toxic to us and work by hormesis. Studies show that our bodies react to polyphenols by trying to neutralise and get rid of them, for instance, by upregulating a gene called Nrf2, which controls a wide range of cellular defence mechanisms. This gene is also upregulated after radioactive radiation.
Hormesis in animals
Long-lived birds don’t have less oxidative stress than shortlived birds. And naked mole-rats have at least as much oxidative stress as their shorter-lived cousins, mice. In general, naked mole-rats seem to live a long time not because they are stress-free but because they are sublimely equipped to deal with stressors. Whether it’s exposure to DNA-harming chemicals, low oxygen levels, ingestion of heavy metals, or exposure to extreme heat, naked mole-rats fare far better than mice. It seems the secret to a long life is not to live without difficult times, but to be able to withstand the onslaught.
You can consider eating lots of plants as a safe and superior alternative to ingesting toxins. How about a safe and superior alternative to moving into a radioactive apartment? One idea would be to get high up in the mountains. The atmosphere is thinner at high altitudes, and that means you’re less protected from the sun’s UV rays as well as being exposed to cosmic radiation. I can attest to that as a pale inhabitant of one of the flattest countries in the world having got the sunburn of a lifetime at an altitude of five kilometres.
It might not be surprising to you anymore, but despite the radiation and harsh conditions – or because of them – people who live at high altitudes tend to live longer and experience fewer age-related diseases than those who live at sea level. This has been noted in both Austria, Switzerland, Greece and California.
At higher altitudes, there is also lower oxygen levels than at sea level, and this too might play a role as a health-promoting stressor. At least, one of the reactions your cells have to both radiation exposure and low oxygen levels is the production of something called heat shock proteins. As the name suggests, these proteins were originally discovered in connection to high heat, but it turns out they are part of a more general suit of cellular protective mechanisms. Just as we have seen before, this illustrates that hormesis is often far-reaching. The response to one stressor will tend to improve resilience against other stressors, too.
You can think of heat shock proteins as a sort of protein superhero that helps other proteins. When cells are damaged by some kind of stressor, many proteins end up in the wrong shape. But heat shock proteins help them recover their form and function so that they don’t turn into cellular junk.
Interestingly, the namesake of the heat shock proteins, heat shock, is not restricted to laboratory animals. It’s an integrated part of Nordic culture in the form of the sauna. The homeland of the sauna, Finland, has blessed us with more sauna studies than we could ever have asked for. And in these studies, sauna use tends to correlate with various health benefits – a lower risk of cardiovascular diseases and a longer lifespan, for instance. Heat shock proteins probably play a role in these health benefits, but there are also other beneficial effects from sauna use, such as lowered blood pressure. (When it comes to the sauna, there is a small ‘but’ to bear in mind, though: men who want to be able to have children should not spend too much time in the sauna, for the same reason that it can be a bad idea to spend long stints in hot tubs, or to sit with a laptop in your lap.)
Besides heat exposure, another integral part of Nordic culture is cold exposure in the form of winter swimming. Actually, the two are often undertaken in a single session, with a cold dip interchanged with sauna stints. We don’t have the same amount of data on the benefits of cold exposure as we do on sauna use. But it is easy to imagine cold exposure could also have long-term health benefits. For one, it activates something called ‘brown fat’, which works in the opposite way to normal fat. It’s for burning energy, not storing it – in doing so it warms us up. And interestingly, it turns out that many long-lived species have naturally increased activity in their brown fat tissue. Proof or not, the hardcore winter swimmers I know swear by the effect. They notice an increase in energy, fewer sick days and report a general feeling of wellbeing. After the swim, that is.