Starving for Fun
Imagine we’re transported back to Venice in the 1400s. We’ve gone far enough into the past that the country of Italy doesn’t exist yet. Instead, Venice is an independent and incredibly rich city-state. The city produces everything from silk to cotton and glass, and the merchants of Venice distribute exotic goods throughout Europe. Its copious wealth and huge seafaring fleet has made Venice one of Europe’s unconditional centres of power.
Among the beautiful canals, we may be lucky enough to encounter a nobleman named Luigi Cornaro. While Cornaro began his life with modest means on the mainland, he later built a fortune by inventing methods for draining wetlands: not a bad occupation in the Venice area.
Cornaro used his fortune to enjoy a life of abundant food and drink, but by the age of forty, this decadent lifestyle had begun to catch up with him. He was overweight, sluggish and feeling old. Ever the innovator, Cornaro decided to take matters into his own hands. And so began a fanatical hunt for a healthier lifestyle.
After consulting with a few doctors, Cornaro came up with a new diet, following a set of strict rules. He’d eat no more than 350g (12¼oz) of food a day, made up of eggs, meat, soup and a little bread. And – naturally, for an Italian – a little wine, too. But only around half a bottle a day.
This new restrictive diet plan worked wonders for Cornaro’s health. He was so amazed with his progress that he decided to write a book about his new diet to spread the word. It was, appropriately, titled Discorsi della vita sobria – ‘Examination of the sober life’.
The book was a huge success and was quickly translated into several other European languages. As for Cornaro himself, he never strayed from the diet again. However, he did continue to experiment, and went on to write several more books on the subject, including The Art of Living Longer, which he penned at the age of eighty-three.
By the end of his life, Cornaro had restricted his diet to a single egg yolk at each meal. While not terribly exciting, it seemed to work better than ever. Cornaro was so healthy that he continued his authorship well into his nineties.
When the Grim Reaper finally came knocking on his door, Cornaro had lived the equivalent of two medieval lives, reaching the remarkable age of somewhere between ninety-eight and 102 years old.
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Nearly four centuries after Luigi Cornaro’s death, an American professor was led down the same path as the Venetian nobleman.
Researcher Clive McCay, who we met while discussing young blood, was a professor at Cornell University in New York State and an expert on nutrition. Back in his time, in the 1930s, there was a lot of focus on helping children grow, preferably as fast as possible, and using vitamins, which were a recent discovery at the time. This zeal for growth worried McCay. He believed that it was better for a person to grow slowly if they wanted to live a long and healthy life.
His inspiration? An English scientist from the sixteenth century with the fitting name of Lord Francis Bacon. Bacon wrote in one of his books exactly what McCay claimed: if you want to live a long life, it is not about growing fast, but about growing as slowly as possible. Preferably to a small adult size. Sound familiar?
To test his theory on growth and longevity, McCay designed an experiment using rats. He divided the rats into three groups. The first group was fed normally, while the other two were fed a diet with significantly fewer calories than normal. McCay made sure the rats weren’t malnourished – they got all the vitamins and minerals they needed – just not enough calories. This type of diet has later been named ‘calorie restriction’.
As time went on, the rats in the experiment began to die, and McCay attentively noted their lifespans. After 1,200 days, only thirteen of the original 106 rats remained. Every single one of these rats was from one of the calorie-restricted groups. At the time, they had the dubious honour of being the oldest ever laboratory rats.
The rats seemed to prove McCay’s theory. Calorie restriction made them grow more slowly, and ultimately end up smaller, while also prolonging their life.
However, decades later, in the 1980s, two scientists, Richard Weindruch and Roy Walford, discovered that growth impediment isn’t actually necessary. Calorie restriction still prolongs the life of rodents even if they are allowed to grow to a normal size before their calorie intake is cut down.
Weindruch and Walford also proved that there is a linear relationship between how much you limit calories and how much longer rodents live. Mice fed in abundance live the shortest lives. Mice that are somewhat calorie-restricted live longer. And so it continues until we reach the longest-lived mice of all: those that have been calorie-restricted almost to the point of starvation.
Incidentally, Roy Walford ended up trying calorie restriction on himself.
In 1991, he was part of the first team inside Biosphere 2, the giant futuristic greenhouse, remember? The goal of Biosphere 2 was to create a closed ecosystem that could provide humans and animals with everything needed to sustain life. Walford and his team were locked inside the closed ecosystem for a full two years. As it turns out, building an entire ecosystem from scratch is really hard. The Biosphere 2 team had to drastically cut back their food intake, and eventually required assistance from outside. Over time, it became acceptable to finish each meal by licking the plate clean.
I’m sure you aren’t particularly jealous to not have gotten the offer. But for Walford, these conditions were a scoop. His time inside Biosphere 2 allowed him to test calorie restriction on humans and the results were confirmatory. During their famished stay in Biosphere 2, all members of the scientific team had lower blood cholesterol, lower blood pressure, and better immune systems than they’d had before the big experiment.
Since these early studies of calorie restriction, the effect has been proven many times over. When rodents have their calorie intake limited, they typically live between twenty and forty per cent longer than normal. In addition, the animals can reproduce for a longer period of time, have stronger immune systems, are less likely to be affected by cancer and also tend to look younger than age-matched controls. However, we know research done in rodents doesn’t always translate well to humans (and sometimes not even to other rodents . . .).
In an effort to get data more applicable to humans, two research groups in the United States have used rhesus monkeys instead of mice or rats. Rhesus monkeys can live for over forty years, so these experiments were a long ordeal. They were started in 1987, and it’s only within the last ten years that the results have begun to come out. Were they worth the wait?
When you choose to spend over thirty years on a research project and do precisely two different studies, Murphy’s Law dictates that they’ll have to give conflicting results. And that’s exactly what happened. In the first study, the answer was yes – calorie restriction extended the lifespan of the rhesus monkeys. In fact, one of the monkeys ended up setting the species record for longevity. In the second study, however, there was no particular life extension, although the calorie-restricted monkeys did seem to be healthier while alive.
The conflicting results make it hard to conclusively say whether monkeys fed fewer calories live longer. And we probably shouldn’t anticipate that a few million dollars will be set aside for a new experiment with an end date in the middle of the century. So, what can we do to find out if calorie restriction works in humans? It would be pretty difficult, as well as fairly unethical, to do these kinds of studies in humans. Any volunteers to starve?
We do have natural experiments, such as the one from Biosphere 2, of course. And beyond that, there is actually such a thing as calorie-restriction enthusiasts. The ‘Calorie Restriction Society’ is a group of people who practise voluntary calorie restriction. Of course, humans live even longer than rhesus monkeys, so it’s too early to say whether the members of the Calorie Restriction Society all end up with biblical lifespans. However, studies on these people have shown that their risk parameters for everything from diabetes to cardiovascular disease are absolutely excellent. There’s no doubt they are a bunch of unusually healthy people.
Besides these natural experiments, there have also been a few actual trials of calorie restriction. In one example, participants were divided into two groups: group one was told that they should continue to eat normally, while group two was asked to cut their calorie intake by twenty-five per cent over the following two years. Of course, it turned out to be virtually impossible to cut down food intake that much voluntarily. But by the time the two years were over, group two had still managed to reduce their calorie intake by twelve per cent.
Although that’s a smaller reduction than planned, it still proved to be enormously beneficial for the participants. Group two members showed improvements across the board. In fact, the changes were reminiscent of those seen in Calorie Restriction Society members, and of the laboratory animals used in calorie restriction research.
Have I convinced you to voluntarily starve? Probably not. For the vast majority of people (including myself), the benefits just aren’t great enough.
First, there’s the uncertainty – how well will calorie restriction work in humans? In general, it seems that the longer an animal normally lives, the less effectively calorie restriction works. That is, it works great in worms, fine in mice, okay in rhesus monkeys and maybe in humans. This is the pattern most life-extension interventions show, actually. I would guess calorie restriction could increase the lifespan of a person by a few years at most – and that’s if you know what you’re doing.
Second, the reports from the subjects aren’t very pleasant. Many report feeling cold, sluggish and fatigued. That’s probably how the experimental animals feel, too. Calorie-restricted mice eat like voracious predators if given access to extra food. I guess you could say that it’s unsure whether calorie restriction works in people but it will certainly make it seem like life is very long.
But while the benefits of calorie restriction may not outweigh the disadvantages, the results of these studies can still be useful to us. For one, they teach us that it’s important not to overeat. We might not want to starve ourselves, but there’s no reason to eat beyond being full. More importantly, though, we have learned a new strategy for combating ageing. We might not want to employ it as it is, but maybe we can find a way around the drawbacks. Researchers are currently trying to identify ways to mimic the effect of calorie restriction without actually starving. If we can find out exactly how calorie restriction affects animals physiologically, we can develop drugs or treatments that mimic the effect.
These kinds of drugs are called calorie restriction mimetics. We’ve actually met a couple of candidates already: rapamycin and spermidine. But there are also natural ways to replicate the effect of calorie restriction. And that’s the second possibility – an approach hidden in wisdom from earlier millennia.
Mechanisms of calorie restriction
There’s a lot of research into exactly how calorie restriction works and why it prolongs life. One interesting finding involves the laboratory worm C. elegans. It turns out calorie restriction only extends the lifespan of C. elegans if the worms’ autophagy, cellular garbage collection system , is functioning. If scientists block autophagy, calorie restriction no longer helps the worms live longer. Another hint pointing in the same direction is that calorie restriction doesn’t provide additional benefits in experimental animals on rapamycin. Rapamycin, as you might remember, blocks the growth-promoting mTOR and so activates autophagy.