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ETERNAL LIFE

Hydra is not just the name of a many-headed mythological monster. It is also the name of a very special freshwater polyp. This little animal appears to be an exception to the rule that everything ages. This is due to its extraordinary ability to repair itself after sustaining damage. Humans have only a limited capacity for regeneration and repair. Many types of damage are irreversible — like the loss of a finger, for example. However, some people have an above-average capacity for damage repair. They live longer than others and get sick less often. Although human beings will never become immortal, we can postpone the effects of ageing caused by damage.

In summer, ponds burst into life. Marsh marigolds flower, dragonflies flit over the surface of the water, and the pond edge offers nesting sites for many species of bird. A child’s fishing net is enough to scoop all manner of wildlife out of the water: sticklebacks, for example, but also hydras — a kind of freshwater polyp.

The hydra belongs to the family of animals known as Cnidarians, which also includes corals, jellyfish, and sea anemones. Hydras are about half a centimetre long, with a tube-like body. In fact, they are little more than a large gut, with a head at one end and a tail at the other. At the head end, the hydra has a set of tentacles that it uses to catch its prey. It has been claimed that hydras are immortal. The animal’s name refers to the many-headed monster of Greek mythology whose lair was in Lake Lerna, at the entrance to the Underworld. According to legend, the serpent could not be killed, because for every head that was cut off, it grew two more. Finally, it took the superhuman powers of the hero Hercules to slay the beast, which he did as the second of his Twelve Labours.

Like its mythical namesake, the hydra from the pond is also in fact mortal. If it is removed from the water and placed in the sun, it will dry out and die. One gulp from a stickleback, and a hydra is history. Nothing remains of the myth, but, still, there is no doubt that the hydra is an extraordinary animal.

DAMAGE AND REPAIR

In the late nineties, the biologist Dr Daniel E. Martínez decided to really put these hydras to the test. He filled an aquarium with water containing a large number of hydras, and waited to see what would happen. According to a rigid routine, the hydras were fed, the water changed, and the temperature adjusted to make sure it remained constant.

Not much happened. Clinging to the bottom of the tank with their ‘feet’, the polyps swayed back and forth, waving their tentacles around to catch food. Very occasionally, on inspection in the morning, a hydra appeared to have died. It was a rare occurrence, which did not increase in frequency as the years passed. Martínez spent four years observing the fortunes of his hydras. Then he decided it was time for a holiday, and left a colleague looking after his aquarium.

Returning from his holiday, Martínez found that all his hydras were dead. Had they been overfed? Or underfed? Was the water too warm, or too cold? Nobody knew.

However, the unfortunate fate of the hydras led to a major scientific observation, from which two conclusions can be drawn. First, the claim that hydras are immortal was demonstrably false, in spite of the Greek legend. Hydras do not live forever. The second conclusion that can be drawn is more interesting. If, during the four years the hydras were under observation, one occasionally died, and the number of deaths did not increase as the creatures got older, their chance of dying had to be constant over time! Their risk of death did not increase with increasing age, as it does for beer glasses, rubber bands, washing machines, and human beings. Up until Martínez’s fateful holiday, his hydras were no more likely to die at the age of four years than they were at four months or at four weeks. Also, a four-year-old hydra looked exactly the same as a four-month-old and a four-week-old specimen. Based on this information, Martínez drew the remarkable conclusion that hydras do not age. Having been persuaded that all lifeless matter and all living creatures are doomed to become increasingly fragile and delicate with increasing age, we were now faced with the fact that some organisms do seem to be able to escape the ageing process.

When Martínez’s research group published a paper on their results, it caused quite a stir in the scientific community. His conclusion was described by many as implausible. His fellow researchers vigorously disputed his conclusion, arguing that there had to be an alternative explanation for his observations. One suggested explanation was that the period of study was too short, and so an increase in the risk of mortality had been overlooked. Martínez reasoned that four years — four times four seasons — was a respectable lifetime for such a little creature, and that signs of ageing would have been observed over that period if they had been there. Other organisms of comparable size and living in similar environments definitely show features of ageing. However, this comparison was apparently not convincing enough to change the minds of Martínez’s critics.

In science, a lone observation is as useful as no observation at all, because, according to the traditional scientific method, results must be tested and confirmed, or else disproved, by other laboratories. As it turns out, many initial results claimed in leading scholarly journals cannot be replicated by other researchers — not because the reported results were made up and the scientists who published them deserve to be unmasked as frauds, but because unusual, one-off events can occur during any testing process. If this turns out to be the case, the results cannot be confirmed, no regularity in them can be claimed, and there is no reason to add them to the body of current scientific knowledge. Since 2005, scientists at the Max Planck Institute in Rostock, Germany, have been studying two thousand hydras in the institute’s tanks. They want to find out whether there is any scientific predictability to Martínez’s results. Eight years have now passed, and, while the occasional hydra dies now and then, the number of deaths has not been observed to increase as the polyps’ age increased over time. And the hydras still look the same as they did at the start of the experiment!

How is it possible that a hydra in a laboratory tank can live to a great age without any permanent damage accumulating in its body, and can avoid falling prey to the ageing process? If a lab-tank-dwelling hydra is cut in two — a radical experiment of the type often carried out by mischievous boys on earthworms — both halves will develop into a complete hydra. The head grows a new tail, and the tail grows a new head. Unlike mice and men, hydras appear to have huge regenerative abilities. In other words, when damage to its body occurs that cannot be repaired, the damaged tissue is simply replaced. In a similar way, a salamander can regrow its tail after losing it in a tussle with a predator. We humans, however, who also sometimes lose an arm or a leg, have to face the rest of our lives without the missing limb. Our bodies have a ‘segmental’ regenerative power: certain tissues can be replaced, but others cannot. If up to a tenth of the human liver dies or is removed, the organ will grow back to its normal size. Our skin flakes off every day; luckily, there are stem cells in the deepest layers of our skin that replenish it layer by layer. The same happens in the gut, where the ‘inner tube’ is regularly worn away. This regenerative ability of cells, tissues, and organs stops hydras from ageing and keeps them looking ‘young’. We now know that hydras have ‘totipotent’ stem cells with an unlimited capacity to divide and produce cells that can be used to rebuild any kind of tissue, and even an entire body.

This means that no damage, whether external or internal in cause, has lasting consequences. But if all the stem cells that make up a hydra are lost at the same time — for example, when it is removed from the water, placed in the sun, or gulped down into the stomach of a stickleback — the animal turns out to be mortal after all.

It seems almost inconceivable that a hydra can carry on regenerating for its entire life. In fact, such regeneration is the most common way these polyps reproduce. By cloning one single cell, they grow a bud on the outer wall of their bodies that develops into a new individual. When it breaks away from its parent body, the clone can live independently. We humans do not possess this ability, of course. Nor can we always completely repair damage we have sustained, as we simply do not have the necessary regenerative powers. This means such damage is permanent, and permanent damage accumulates over the years. Our bodies and our brains become frail and vulnerable. We get biologically older, while hydras remain ‘forever young’.

Knowledge of the limited capacity of cells, tissues, and organs to regenerate has given scientists an insight into the direction they need to take their research if they are to find a way to slow, or even halt, the ageing process. For instance, Parkinson’s disease is known to be caused by the death of a small set of highly specialised brain cells, known as the substantia nigra. This results in a shortage of the neurotransmitter dopamine in the brain. As a result, patients with Parkinson’s are sluggish and stiff, and subject to involuntary movements such as tremors. Treatment for Parkinson’s currently consists of prescribing drugs that increase the concentration of dopamine in the brain. The results of this treatment are good, but it cannot remove all the symptoms of the disease, and is associated with side effects. In fact, the drugs increase the level of dopamine in the entire brain, and not just the substantia nigra, where low levels lead to Parkinsonism. It would be wonderful if, in the future, scientists are able to grow a new set of highly specialised dopamine-producing cells from a sample of the patient’s own stem cells. If such cells can then be introduced into the substantia nigra and persuaded to take up their normal function there, Parkinson’s disease will become a thing of the past.

From a biomedical point of view, old age is necessarily associated with lasting damage to our body. Some damage is greater than other damage, but what is more important is that some damage can be repaired, and some cannot. A shattered bone in the lower leg — sustained perhaps in a motorbike accident — will hopefully leave no lasting effects that might be detectable in years to come. But a missing tip of the middle finger of your left hand — after a careless moment with the electric saw — will never grow back. We simply do not possess the regenerative power to replace an entire joint of our finger. We do have some medical tricks up our sleeve: when the lenses in ours eyes become so clouded by cataracts that reading is no longer possible, even with the aid of spectacles, modern ophthalmologists can replace them surgically with artificial lenses.

Just as ageing can be seen in the state of our eyes, other parts of our bodies and brains can sustain damage that can be repaired or reversed to varying degrees. Genuine flu is associated with terrible muscle pain and high fever, and the virus causes a lot of damage. It is not without reason that a bout of flu leaves us out of action for some time. After a couple of weeks, however, everything is back to normal. Not all viral infections have such a favourable outcome, and some cannot be overcome without leaving permanent damage. The measles virus, for instance, can cause lasting abnormalities in the brain, and the polio virus can lead to permanent paralysis. The damage caused by the human papilloma virus (HPV) can lead to cervical cancer in the long term. This is why we have vaccination campaigns for measles, polio, and HPV: they offer the only protection against lasting damage.

The above examples might make us think that all the damage incurred by our bodies comes from external sources — accidents or infections. This leads us to seek out ways in the world around us to help us stay healthy longer, since someone who manages to avoid any kind of stress or infection throughout her life will also suffer less damage. It is true that it pays to be cautious. But this does not mean that cautious people sustain no damage in their lifetime. Every time a joint in our body moves, two layers of cartilage rub against each other. They are extremely smooth and elastic, and they are very well lubricated, but even all this cannot completely prevent wear and tear. Knees and hips are particularly notorious for this, and many people suffer greatly with them in old age, because the cartilage in those joints has simply worn away. The stem cells in the deepest layers of cartilage, the source of growth and repair, are exhausted. This means that the layers of cartilage above them gradually wear away, and eventually leave bone grating against bone. Doctors call this loss of cartilage ‘osteoarthritis’. It is not only knees and hips that can be affected; shoulders and even the joints in your fingers can be stricken with osteoarthritis — as can, in fact, any part of the body where cartilage is found, including the back. Wherever the health of a joint is compromised by abnormal development, growth, or an accident, cartilage is lost even more quickly, because the remaining cartilage in the joint is then additionally stressed by overuse. In this way, one kind of damage can cause or exacerbate another.

Does this mean, then, that we should always be cautious, and spend our lives just sitting still? No, because even when we are at rest, our body is in action. Although the muscles in our arms and legs might be at rest, the same is not true of our rib cage, which we use to breathe, or of our heart, which must constantly pump blood around our body. And what about the valves of the heart, which open and close with every heartbeat? Careful examination has shown that the valves of most older people’s hearts are leaky and constricted. This often causes no negative symptoms; but, whether it goes unnoticed or not, the damage is there.

LONGEVITY IN FAMILIES

The idea of wear and tear is the basis for the popular but erroneous ‘rate of living’ theory. The reasoning is that a knee is built to bend a particular number of times and no more, and that the valves of the heart can open and close only a pre-determined number of times. When the maximum number of bends or heartbeats has been reached, it’s over: the organ is broken, the body is sick, and the person dies. Proponents of this theory often point to the hummingbird as an example. It has a very rapid heartbeat and a short life. But one observation does not make a rule of biological science. A hypothesis can only be said to be substantiated if the postulated connection is observed repeatedly in different species. According to this, if the rate-of-living theory were true, it would mean athletes are busy shortening their lives by a significant margin as they train. Every time they exert themselves, athletes raise their heart rate to an exceptionally high level, after all. But, instead of shortening their lives, the repeated exercise that athletes take improves their physical fitness, and, for most of them, this results in a longer, not a shorter, life.

From a medical and biological point of view, it is also hardly conceivable that the rate-of-living theory could be correct. After all, as we go through life, our bodies do not only accumulate damage; they also have the ability to repair it. The body is more than just a passive punching bag that absorbs every blow, and slowly declines. The body can respond; it tries as best it can to repair any damage it sustains; or, where possible, to replace tissue without leaving lasting damage or scars. All the indications are that regular physical exertion stimulates our body’s abilities to repair itself, so that, despite the increased physical stress the body is exposed to, the balance between damage and repair is positive, and lasting damage is less likely to occur.

Hydras appear to be able to repair all the damage their bodies sustain, but that may be because a hydra’s body is not very complex. Humans’ ability to repair tissue and organs is very different. It is logical to conclude that a great ability to repair cells, tissues, and organs contributes to longevity, and that the capacity for repair is contained in our DNA, our genes. This means that it is ‘embedded’ in us, and is one of the things that influences how long we live, on average. A greater capacity for repair would certainly extend our lifetime, giving us more years to experience the journey of life, but this is something that is not granted to us as a species. However, we have no reason to lament this state of affairs. Our bodies do have a great capacity for repair, and that is one of the reasons why we live considerably longer than mice, cats, and dogs do.

In some families, thrombosis, cancer, or mental illness occur more often than the average. Such families are genetically predisposed to this, since the structure of their DNA means these conditions are more likely to develop, and are more likely to appear earlier in life. This can be compared to a congenital defect. But the opposite also occurs: members of some families not only live to an extraordinarily great age, but they also develop few or no illnesses. One explanation for this might be that they have lived extremely careful lives, and so managed to avoid any serious accidents or infections. But it may also be the case that members of such families are genetically equipped with an above-average capacity for repair, and so incur less lasting damage, fall ill less in later life, and remain healthy for longer.

The idea that some families have an above-average capacity for damage repair is currently being tested in research. Scientists in Italy and America are studying the 60-to-80-year-old children of centenarians, and comparing these ‘children’ to their peers from the general population. This research aims to investigate the differences between two groups of adults that could explain above-average longevity.

But what if the fathers or mothers of these people were just lucky, and none of their aunts and uncles lived to great old age? There would be nothing special about that. In order to be certain that longevity has a biological basis, professor of molecular epidemiology Eline Slagboom and I took a different approach. We identified families as exceptional only if a nonagenarian had at least one living sibling who was also over 90. Looking at a photo of a whole set of such older brothers and sisters, anyone would exclaim, ‘This can’t be a coincidence — there must be something special about that family.’ And it is this ‘something special’ that we are searching for.

As part of the Leiden Longevity Study, some four hundred of these particularly long-lived families were monitored between 2002 and 2005. It was not only the nonagenarians who were asked to take part in the study, but also their grown-up children and their partners. We drew up their pedigrees and compared mortality in these families with that of the general population. An analysis of these figures showed that every generation of the families under investigation had a 30 per cent lower chance of dying at any given age than the average in the Netherlands. That translates into an extra six years of life expectancy. We also investigated members who had joined the family through marriage — the ‘in-laws’, so to speak. As we expected, these relatives by marriage appeared to have no survival advantage; they reached the same age as the average Dutch person. This strict division along bloodlines in the ability to live longer indicates that there is a genetic predisposition for longevity.

The 50-to-70-year-old children who took part in our study were also compared to their partners, with whom they had weathered the ups and downs of life for many years. A similar comparison was not possible with their nonagenarian parents, since most of them had already outlived their partners. At first glance, there appeared to be little difference between the ‘children’ and their partners; similar age, similar size, similar weight. Also, their lifestyles did not appear to differ too much from each other: a little smoking, a little sport, a little drinking. Seen through a biomedical lens, however, there were clear differences. The children of long-lived parents had a significantly lower incidence of high blood pressure, diabetes, and cardiovascular disease. Blood tests also showed that they had a much better risk profile, with lower levels of ‘bad’ cholesterol and blood sugar.

The results from the Leiden Longevity Study are broadly consistent with the findings of those Italian and American researchers who also investigated the children of centenarians. They also found less cardiovascular disease, and lower risk factors such as high blood pressure, diabetes, and high cholesterol levels, among those offspring. The preliminary conclusion from our research is that families that live longer on average have a more efficient metabolism — the body’s energy supply and fuel-combustion system — which means that less damage can occur to their blood vessels and organs.

Thus, damage can be prevented by having a well-functioning metabolism. But, of course, the repair and replacement of cells or tissue when they do get damaged also helps. Some scientists have made it their mission to investigate this aspect, reasoning that damage can never be completely avoided. They have set themselves the goal of finding out whether people born into long-lived families have not only a better metabolism, but also a greater capacity for repair, making them less susceptible to sickness. In short, they want to know whether long-lived individuals are in some ways similar to hydras. And the next question will then be: how can we make use of this knowledge to help us stay healthy for longer?