Chapter 6

Does Size Matter?

The year 1492 was among the most eventful ones in the area that has today become Spain. Two days into the new year, the Muslim Emir of Granada surrendered to the Catholic King Ferdinand of Aragon and Queen Isabella of Castile. The surrender ended the centuries-long reconquista, in which the Catholic kingdoms of the north slowly regained their homeland from Muslim conquerors.

Two weeks after the decisive battle, the two monarchs met with a merchant from Genoa in present-day Italy. For years, this merchant, Christopher Columbus, had been requesting they support his idea: finding a sea route to Asia by sailing west. In return for their support and funding, he promised that the new route would bring the monarchs and their kingdoms enormous wealth.

We don’t know why – maybe it was the optimism of victory – but that year, the monarchs agreed to fund Columbus’s journey. Soon, three Spanish ships set sail and headed west across the Atlantic. After a long journey, they landed on the American continent as the first Europeans since the Vikings.

Meanwhile, King Ferdinand and Queen Isabella were also plenty occupied at home. After centuries of religious and territorial conflict on their peninsula, they wanted their new kingdoms to be completely Christian. In what’s called the Alhambra Decree, the Spanish Jews were given an ultimatum: convert to Christianity or leave the country. Some chose their home over their faith and became converts or conversos. The rest made the opposite choice and ventured out in search of a new home.

The following year, Columbus and his crew returned from the Americas. They initially thought they had been to Asia, but over time, it became clear that the Spanish had reached a continent that was unknown to Europeans at the time. Soon, the Spanish colonisation of the Americas was underway. Spaniards from all walks of life – farmers, criminals, families, priests, soldiers, nobles and prostitutes – set off towards the new continent. Among those emigrants were also conversos, descendants of the converted Jews. Despite their conversion to Christianity, they were still discriminated against in Spain, and hoped to become free in the New World.

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In 1958, the Israeli physician Zvi Laron and his colleagues began studying a special group of patients. All of them had dwarfism, though not in the way you might imagine it. Sure, Laron’s patients were short, about 120cm (4 feet) tall. But they didn’t have the body proportions associated with the most common form of dwarfism, such as short limbs and a proportionally larger torso and head. The patients simply looked like scaled-down versions of regular people.

Laron and his colleagues spent eight years carefully investigating the cause of this new syndrome before they could share their results. It turns out patients with Laron syndrome, as it is now called, are short because of a genetic mutation involving growth hormone. The defect is not found in the ­hormone itself, though. In fact, patients with Laron syndrome have quite a lot of growth hormone in their blood. The reason they don’t grow taller is a defect in the growth hormone ­receptor. That is, the receptor that is responsible for the cell sensing and responding to the growth hormone. You can appreciate the ­mechanism through an analogy. Imagine the cell as a castle ruled by a ­powerful, but paranoid, nobleman. The nobleman won’t let outsiders in, so if someone wants to reach him, they will have to shout their message to the guards in the castle tower. Under normal circumstances, the guards will go to the nobleman and recite the message so that he can give his orders. But if the guards are deaf, they won’t hear the message, no matter how loudly outsiders try to scream at them. And then the nobleman will never receive it or respond.

In a similar way, the signal from growth hormone never reaches the cells of patients with Laron syndrome. Their ­defective growth hormone receptors mean growth hormone can float around in the blood at high concentrations without ever inducing growth.

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Nearly 500 years after the Spanish first set foot in the Americas, a newly trained physician in Ecuador was pondering a mystery from his childhood. Jaime Guevara-Aguirre, as he is called, remembered meeting a curious number of people with dwarfism while growing up. With his newly acquired medical degree in hand, he was ready to find out why. The quest took Guevara-Aguirre back to his home region in the mountainous Loja province. Here, he had to travel on horseback to reach his desired destination: some remote villages deep in the mountains. The trouble proved worthwhile, though, and just as he’d recalled, Guevara-Aguirre encountered several people who looked like miniature versions of their relatives.

The explanation is that all these people had Laron syndrome. Without knowing it, they were distant relatives of Zvi Laron’s patients in Israel. You see, the Ecuadoreans with Laron syndrome are partly descended from the Spanish Jews who converted to Christianity and later took part in the colonisation of the Americas. Zvi Laron’s patients in Israel, on the other hand, are descended from the Spanish Jews who made the opposite choice, leaving Spain to keep their religion. While the winding paths of history have driven the two groups apart, the Laron discovery has pulled them right back together. We now know that one of their ancestors must have had a mutation in the growth hormone receptor. To actually get Laron syndrome, though, it is not enough to inherit a single defective version of the growth hormone receptor. If this happens, there’s still a functional version from the other parent and the affected person will just be a few centimetres shorter than normal. But inherit defective growth hormone receptors from both your parents and you have no functional ones. Then you get Laron syndrome. This is the reason the syndrome is rare in Israel today. It’s unlikely for two people to both carry the mutation and pass it on to the same child. In the remote villages of the Loja province, though, Laron syndrome is much more common. The reason is the same one we saw among the Amish of Berne. The region is isolated and was originally settled by a small group of people. Later, the population grew from these few people intermarrying again and again while expanding their numbers.

So Jaime Guevara-Aguirre had found the perfect place to study Laron syndrome. He wasted no time, and before long he made a remarkable discovery. It turns out people with Laron syndrome almost never get cancer. In the entire time these people have been studied, only a single cancer case has been noted. Cancer is characterised by excessive growth (of the tumour), so it sounds reasonable that lack of growth signals would be protective. But people with Laron syndrome actually don’t get other age-related diseases either. They’re protected against cardiovascular diseases, dementia and diabetes. Heck, they don’t even get acne. And all this is despite many Laron people in Ecuador being overweight and subsisting on diets high in processed foods. It’s as if the Laron mutation protects them from disease, even in the face of poor habits.

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In an effort to study Laron syndrome, researchers have bred mice whose growth hormone receptors are also impaired. Just like their human equivalents, these mice are much smaller than average, but have regular proportions. And, like the humans with Laron syndrome, the Laron mice are also remark­ably healthy. In fact, they live much longer than regular mice. Various studies have found that their lifespans are between sixteen and fifty-five per cent longer than normal. If you remember our rule about size and lifespan, this should be no surprise. Large animal species generally live longer than small ones – but within each species, the smallest individuals tend to live the longest. And the Laron mice are about as small a mouse as you can get. Another contender would be Ames dwarf mice that I briefly mentioned earlier. As the name suggests, these mice are tiny too, and they actually have the species lifespan record for mice. Ames dwarf mice are small for a similar reason to Laron mice, though. They have a defect in the pituitary gland just below the brain that means they don’t produce growth hormone at all.

So, how about humans? If smaller individuals tend to live longer in the animal kingdom, does that mean tall people should be worried? Well, the French woman Jeanne Calment holds the world record for longest lifespan at 122 years and 164 days. That is one unusual trait of Calment’s; another is that she was only 150cm (4 feet 11 inches) tall. Just below her on the longevity record list is American Sarah Knauss, who was 140cm (4 feet 7 inches) tall, while further down are Marie-Louise Meilleur, who was the same height as Calment, and Emma Morano, who was 152cm (4 feet 10 inches) tall. To be fair, all of these women were born at a time when people were generally shorter than we are today. But when learning about the longest-lived people, you’ll quickly notice that they would make an extremely poor basketball team – even in their own time.

If we zoom out to population level, the association between height and longevity remains. For instance, remember how we learned that Northern Europeans tend to die earlier than Southern Europeans and East Asians, even though Northern European countries are richer? Well, Northern Europeans are also taller than Southern Europeans and East Asians, so maybe that explains it.

Another example is that American sociologists used to ponder what is called the Hispanic Paradox. That is, Hispanic Americans tend to live longer than white Americans, even though white Americans ‘should’ live longer on paper: they’re richer, more highly educated and have slightly lower obesity rates. But Hispanic Americans are shorter.

A third example is the Blue Zones. There’s Okinawa, which is among the shortest prefectures in Japan, a country whose inhabitants are already among the shortest in the developed world. And there’s Sardinia, which is one of the shortest regions in Europe. The average height for men in Sardinia is 168cm (5 feet 6 inches), several inches shorter than the Italian average, and almost half a foot shorter than the tallest populations in Europe. We know the Sardinian stature is genetic in origin, and interestingly, one of the culprits is the Laron mutation, which is carried by 0.87 per cent of Sardinians. This is among the highest frequencies of the mutation in the world, though obviously lower than among the Ecuadoreans of the Loja province.

Now, all of this doesn’t mean that you’re destined to die early if you’re tall. Or alternatively, that you can expect your shortness to carry you. These things are averages. There are lots of short people who die early and lots of tall people who live long and healthy lives. But on average, there is definitely something about the connection between size and lifespan. And that means it can teach us something about ageing.

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It’s obviously not height itself that ages people. If we compressed you really hard to make you shorter, you wouldn’t suddenly live longer – probably the opposite. So what is it that makes short people live longer than tall people? For one, large people have more cells than small people. That means they have more cells that can become cancerous and thus have a slightly increased cancer risk. However, that is nowhere near enough to account for this phenomenon. Instead, the explanation is probably that height is a sign of how you respond to growth signals. Tallness could mean you have stronger growth signals than others or that you are more responsive to them.

So to discover the secrets of a long life, we need to head down the rabbit hole that is growth signalling. As we saw in the Ames dwarf mice, we start just below the brain in the pituitary gland. This gland releases growth hormone, but despite the name, growth hormone is not actually responsible for growth – not directly, at least. Instead, growth hormone travels to the liver, where it binds to growth hormone receptors. This binding makes the liver produce another hormone called IGF-1 (insulin-like growth factor 1), and it is IGF-1 that actually makes stuff grow. This means Laron syndrome can be treated by synthetic IGF-1, not by growth hormone.

So IGF-1 brings us one step further down the rabbit hole. We can verify that we’re going in the right direction by looking at laboratory organisms. The various long-lived dwarf mice we discussed previously all have low IGF-1 levels. Meanwhile, one of the best ways to prolong life in the worm C. elegans is to inhibit the worm’s own version of IGF-1. And then, of course, we have human evidence from the Laron patients. Unfortunately, these people have a high rate of deaths in accidents because of their small size, so we don’t actually know if they live longer than others. However, as they’re protected against age-related diseases, it would be no surprise.

Now, obviously it’s not certain that you would trade in some of your height in return for a longer life; I guess it depends on where your priorities lie. But blocking IGF-1 could still be useful. Age-related diseases happen much later in life than growth, so it is possible we could block IGF-1 in old age and get both stature and a decreased risk of cancer and other age-related diseases. Perhaps even a longer life.

Ironically, growth hormone – and by extension, the IGF-1 it creates – has been dubbed an ‘anti-ageing’ cure since the 1980s. You see, growth hormone has been a popular ‘supplement’ among bodybuilders since its discovery because it promotes muscle growth. But some older bodybuilders discovered that the injections did much more than that. The growth hormone also made them feel young and bursting with energy – and thus the idea of using growth hormone to combat ageing was born.

Before decrying the irony, it’s important to remember that feeling young and energetic is valuable on its own. But aside from this, there are some things the growth hormone propon­ents are right about. IGF-1 definitely has positive aspects, even when it comes to ageing. It promotes growth of muscles and bones, which is beneficial in old age. Sure, it’s not healthy to look like the real-world equivalent of He-Man, but ­maintaining muscle and bone strength in old age is important. In addition, IGF-1 stimulates immune function, which is also something we want, because our immune systems tend to weaken and lose their punch as we age. This is bad news for fighting infections and cancer.

So clearly, there’s something more going on here than simply ‘IGF-1 = bad’. The problem is that IGF-1 is one of those general-purpose hormones with a ton of functions. Our bodies are very fond of recycling like this. For instance, the hormone oxytocin is involved in bonding between people but is also used in hospitals to induce childbirth because it makes the muscles of the uterus contract.

Because IGF-1 has so many functions we have to be able to tell them apart before we can learn which ones promote ageing. Some researchers have tried to do this in a clever study using C. elegans. The researchers discovered that it is only helpful to block IGF-1 in the nervous system of the worms. If they blocked it in muscle tissue, the worms would die sooner than normal. So all this suggests broadly blocking IGF-1 is not the best idea. Maybe in the future, researchers will succeed in making therapies that target IGF-1 at just the right time and in just the right place to be rejuvenating. But given the mixed signals here, it is a hard target for experimenting. Instead, we should continue down the rabbit hole.