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THE BIOLOGY OF AGEING

The evolutionary explanation for why we age is that people invest in fertility at the expense of their own body. There are countless biological mechanisms that explain how an accumulation of damage in our body can develop into a medical condition, disease, or infirmity later in life. Often, no strict differentiation is made between the ‘how?’ and the ‘why?’ There can be no doubt that human ageing cannot be prevented. But ways of repairing the damage that causes ageing do offer new prospects for the future.

In summer 2012, the Dutch theatre company Cowboy by Night staged a performance called Tinbergen’s Gulls. It was a tribute to Niko Tinbergen (1907–1988), a Dutch biologist who wanted to understand more about animal behaviour. The premiere performance took place on the island of Terschelling, on the edge of the nature reserve where Tinbergen had set up his field laboratory more than half a century earlier, to study the behaviour of herring gull chicks. At that time, behavioural science was a completely new branch of biology, and Tinbergen is seen as one of the founding fathers of behavioural biology. He and two of his colleagues from Austria were awarded the Nobel Prize for Physiology in 1973.

Tinbergen’s experiments on the island go back to the nature-nurture question: the debate among scientists about whether particular biological phenomena can be explained by innate characteristics, or whether they are the result of environmental influences. Tinbergen was fascinated by the behaviour of young gulls. Newly hatched chicks immediately start to peck the red spot on their parents’ beaks. The parents react by regurgitating food for the chicks to eat. Tinbergen theorised that the hatchlings must have a pretty good idea of what a herring gull’s beak looks like before they emerge from the egg. To test his idea, he made a set of cardboard gulls’ heads: some with a red spot on their beak and some without; some with different-coloured spots; and some with a spot on the forehead rather than the beak. He expected to find that chicks most often pecked at the cardboard heads that most closely resembled the real thing. And he was right. The chicks’ pecking behaviour depends on the interplay between the parents, who stick out their heads, and the chicks who recognise the beak without prior experience of it. Stimulated by their parent’s beak, the chicks engage in pecking behaviour, which in turn stimulates the parents to regurgitate food. Just as with all biological phenomena, it depends on a combination of nature and nurture.

That parent birds and chicks should be fixated on each other in this way is not difficult to understand. It increases the chicks’ chance of survival, and so increases the fitness of the whole species. It also explains why this behavioural pattern has evolved over many generations of natural selection and is controlled by the birds’ genes. Biologists refer to a biological phenomenon that is logical and explicable from an evolutionary point of view as an ‘ultimate explanation’.

The gulls’ instinctive behaviour is the result of a whole chain of events. It begins with the chick’s visual recognition of the red dot. This recognition requires the stimulus to be transferred from the chick’s eyes to its brain, which then must process the information. This is followed by a complex coordination of the chick’s body, resulting in its pecking at the beak of its parent. The pecking triggers a gag reflex in the parents, which regurgitate food. The chick then eats the food. All these events are controlled by a complex interplay of nerves, muscles, and organs. Biologists call this a ‘proximate explanation’. A characteristic of such an explanation is the description of the mechanism that explains the pecking or gagging behaviour. This requires an examination of a whole series of events, from perception of the stimulus to the execution of the behaviour. That examination provides an answer to the question of how it happens. The ultimate explanation answers the question of why the animals display this behavioural pattern.

Behavioural research is not only carried out on gulls, but also on other birds, on mice, rats, and on our close evolutionary relatives, the apes. Scientists believe there is no fundamental difference between species when it comes to the control of behaviour.

This idea was also the starting point for the theatre performance on Terschelling. During the show, the actors reconstructed Tinbergen’s experiments in a hollow between the dunes. Then they appeared with bright red lips, shiny high heels, and huge, brightly coloured false hips, and proceeded to simulate sexual acts. The actors wanted to show the audience that our behaviour is also controlled by primeval reflexes and external stimuli. The performance ended with the actors covering up the erotic stimuli, and ‘returning to their senses’. As if to say, ‘Don’t trust your instincts!’

There are also ultimate and proximate explanations for the ageing process. The ultimate explanation for why we age is that we invest in fertility at the expense of our own body. Alongside this one evolutionary explanation, there are countless types of damage that cause a reduction in the functioning of cells, tissues, and organs. Every causal mechanism of disease and infirmity in old age is a proximate explanation for how our body begins to falter. The difference between proximate and ultimate explanations is important because hundreds of theories of ageing have now been formulated. The question is what exactly each theory explains. There are popular theories about the breakdown of proteins, DNA damage, chronic inflammation, a shortage of stem cells, and the crucial role of free radicals and telomeres. The list goes on, and new mechanisms are added to it regularly. I will discuss some of the more high profile of them.

Although most of these theories are presented as the theory of ageing, none of them explain why we age. Thus, they are proximate explanations at best. Furthermore, closer inspection reveals that the indicated mechanism is only able to explain some of the phenomena of ageing. In brief, the biological mechanism described is nothing more than just one of the many types of damage to our body that come together to form an explanation of how we age. The sobering conclusion is that unravelling one biological mechanism is not going to allow us to counteract the human ageing process.

ACCELERATED AGEING

Babies and infants are vulnerable: they are susceptible to low and high temperatures, infections, and accidents. This susceptibility reduces considerably as they get older and continue to develop. With the passing years, their bodies gain strength, and their risk of dying from starvation, dehydration, and accidents falls. Children’s chances of catching many illnesses also go down as they grow up. Resistance to infectious diseases is a good example. Anyone who has had the mumps or measles cannot get them again: once they’ve been fought off, children become immune to these illnesses. The reason for this is that our immune system is so highly developed that it recognises an ‘enemy’ the second time around, produces specific antibodies against the virus, and activates immune cells to kill off those pathogens. All of us catch a whole range of infectious diseases in childhood, which helps our immune system adapt even more closely to our environment.

Since our immune system ages as we do, the probability of getting an infectious disease rises again in old age. Babies and old people have the highest risk of dying from flu. Worldwide, seasonal epidemics are estimated to result in about 3 to 5 million cases of severe illness, and about 250,000 to 500,000 deaths. Vaccination programmes have been put in place to help vulnerable individuals muster sufficient protection against the virus. Without a flu shot, their defences would kick in too late, or not at all, with all the consequences that entails.

Some children are born with an ‘immunodeficiency’ — that is, an inability to produce antibodies or immune cells. From the outset, they suffer from serious infectious diseases that cannot, or can barely, be tackled with antibiotics. They do not have a normal childhood. Complications arise early in their lives, for example when a pathogen has established itself in their lungs or brains. An accumulation of damage takes place, and these children appear to age quickly. Their condition is a ‘developmental disorder’, and this term indicates where the solution can be found: in repairing the congenital defect that causes it. Advances in medical technology mean some immunodeficiencies can be treated effectively, for example by administering antibodies or, more experimentally, with a bone-marrow transplant. It is comparable to the way a repairperson is able to permanently solve a problem with a brand-new machine by replacing one component.

Some children appear to develop normally, until something suddenly goes wrong — the expected growth spurt caused by the sex hormones that trigger puberty does not appear. As a result, they remain considerably shorter than their peers. When they then also start to go grey or lose their hair in their twenties, and their skin begins to develop blemishes and ulcers, they appear suddenly to have turned into old people. This is compounded not long after by the fact that their voices become hoarse and weak, they lose subcutaneous fat, and they end up looking ‘elderly’. When later symptoms including cataracts, adult-onset diabetes, and osteoporosis set in, it becomes clear that these individuals do not have a long life expectancy. Such patients look 80 when in fact they are only 30 or 40 years old. Most die around the age of 50 of a heart attack or cancer.

This pattern of development, illness, and infirmity is called progeria — accelerated ageing. Most progeria patients suffer from Werner syndrome, named after the German ophthalmologist Otto Werner, who described a young patient in 1906 with a type of cataract normally only seen in 80- and 90-year-olds. The symptoms of Werner syndrome resemble the normal signs of ageing, but they appear much earlier in life. A closer examination of the symptoms reveals ever more differences from usual ageing. Although the physical effects of Werner syndrome are considerable, sufferers’ brains are spared. This is very different from the ageing we all experience, which damages all our organs, and which so often entails memory complaints.

Werner syndrome is an example of ‘segmental ageing’, in which not all of the body’s cells and organs are affected by the disease process. In addition, when these patients get osteoporosis, it appears in unusual places, such as the long bones, rather than in the hip or the spinal column. Sometimes, patients with Werner syndrome develop various kinds of cancer during their lives, but it is usually of a rare type that begins in the connective tissue.

Werner syndrome is rare, affecting an estimated 1 in every 100,000 children born. It is more common in island environments, such as Japan and Sardinia. This indicates that it has a genetic basis, because parents in small communities are often related to each other; when that is the case, genetic defects are more likely to be expressed. DNA testing has identified the gene associated with this syndrome. All human cells contain 46 chromosomes, and the genetic code for ‘Werner protein’ is found on chromosome number 8. This protein is involved in the ‘unzipping’ of the DNA molecule so that the code it contains can be read by the protein-producing machinery. If that unzipping does not take place, the code remains hidden and there is nothing for the machinery to read, so the cell stops producing proteins.

In order to study the effect of damaged Werner protein more closely, scientists have taken cells from the skin of patients with the syndrome, and cultured them in the lab. These connective tissue cells behave abnormally in that they suddenly stop growing after a few dozen divisions. Researchers believe this behaviour may be the reason for an inability to replace cells sufficiently, causing the premature baldness seen in Werner patients, for example. Some cells display unregulated growth, which might explain the occurrence of cancer in the connective tissue of people with Werner syndrome.

Now that the genetic defect responsible for the syndrome is known, test models have been developed that involve deliberately inserting this mutation into the genetic material of test animals. In this way, researchers hope to unravel more details of the mechanism that causes the syndrome. There is as yet no targeted treatment programme for Werner sufferers — they depend on the possibilities offered by medical technology to treat or prevent the complications and infirmities that arise early in their lives. Replacing a lens clouded by cataracts is one such measure.

It is interesting to investigate what patients with Werner syndrome can teach us about the usual ageing we all undergo. We learn from them that an insufficient ability to read the genetic code contained in our DNA can be reason enough for the kind of damage to occur that explains some of the phenomena associated with ageing. The research in the laboratory shows that the quality of our connective-tissue cells is closely related to the development of ageing-related disease. However, this does not mean we can also conclude that the reverse is true: that the usual ageing process in humans can be ascribed to a flawed Werner gene. The number of people who carry the Werner gene defect is extremely limited, and ageing is a universal phenomenon. So we must conclude that other causes underlie the usual ageing process.

There are other, much rarer, and more extreme, forms of progeria. For example, one in several million babies is born with Hutchinson-Gilford progeria syndrome, in which the segmental ageing process takes place within a space of just ten to fifteen years.

Patients with progeria make a huge impression on us: at a (very) young age, these children look almost like 70- and 80-year-olds. But that little word ‘almost’ is key. Progeria is a congenital abnormality that makes these little patients sick. This is different from the usual ageing process that occurs due to damage, of various origins, which begins to accumulate gradually in the body after puberty.

OXYGEN RADICALS

One of the most popular theories on ageing has to do with the damage that free radicals can cause to the tissues in our body. Many cosmetic products are developed on the basis of this hypothesis. Radicals are atoms or molecules that have a single, unpaired electron in the outermost shell. Electrons, however, like to exist in pairs, so radicals will often bind aggressively with any biological structures in their neighbourhood. When a radical binds to another molecule, it steals an electron from it, causing the affected molecule to become a free radical itself, and a chain reaction occurs. This creates a connection between the entire internal structure of cells and tissues. It is somewhat similar to the way rust forms: iron combines chemically with oxygen, and the rusting process eats up more and more of the original iron. This is also exactly what happens in the ageing process.

One example of a typical radical is superoxide — an oxygen radical — which arises as a by-product of metabolism in cells. Hydrogen peroxide is another example; we know it as an aggressive substance used to bleach hair, for example. Radicals are used by our immune cells to kill off pathogens. At the same time, this immune reaction causes damage to our own body, which then switches on a large number of so-called ‘antioxidants’ to deactivate free radicals. One example of such an antioxidant is ascorbic acid, more popularly known as vitamin C.

The relation between oxygen radicals and ageing was first reported in the nineteen-fifties by Dr Denham Harman, an American gerontologist. It was known that, although it is absolutely essential for life, oxygen at high pressure can cause side effects. This was discovered when high concentrations of oxygen were added to the air given to patients receiving artificial respiration. Their lungs were soon completely destroyed. In combination with the ‘rate of living’ theory, which suggests that a body can tolerate only a certain amount of damage during its lifetime, this led to the ‘free-radical theory of ageing’. The central concept of this theory is that the speed of a person’s metabolism has an influence on how long she will live, just as the size of a candle’s flame determines how quickly it will burn down. In the ensuing years, many researchers have demonstrated connections between the number of free radicals a body produces and the processes of countless diseases such as cancer, atherosclerosis, osteoarthritis, diabetes, as well as degenerative neurological diseases, including dementia.

Radicals can cause irreparable damage to DNA, and that is the first step towards cancer. Radicals also damage the protein called elastin — the ‘elastic’ in our skin — making it less taut as we age. And many more kinds of damage exist. There is absolutely no doubt among scientists that oxygen radicals harm the body, but the crucial question — which has not yet been answered once and for all — is to what extent reducing oxidative damage can slow down the ageing process and prolong our life.

Although radicals are extremely unstable — they arise suddenly and disappear again just as quickly — our body has a large number of antioxidants available to catch and neutralise them before they can cause damage. Recently, experiments were carried out with nematode worms and fruit flies, in which their bodies’ ability to produce antioxidants was switched off using genetic manipulation. It was to be expected that this would lead to an increase in the number of free radicals in the body, causing more damage to accumulate, and thereby shortening the animal’s life. However, the last effect did not turn out to be the case. In most cases, the genetic manipulation did not have any effect, and some of the experiments even resulted in seemingly longer lifespans for the worms and flies.

There is a huge amount of interest among the general public in antioxidants that occur naturally in food, such as vitamin A, vitamin C, vitamin E, and beta-carotene. These substances form the basis for many diets and approaches presented as ‘healthy’. The Moerman Diet is a well-known diet from the Netherlands, and the US-based Nobel Prize laureate Linus Pauling, and others, have advocated taking large amounts of vitamin C or E.

However, while there have been many studies that show a connection between the use of vitamin-rich food and health, they do not allow us to infer a direct causal link between the intake of extra vitamins and health. To this day, many, many randomised studies in which half the subjects are given pills containing extra vitamins, and the other half receive pills containing no vitamins, have delivered no consistent proof that taking vitamin supplements has any advantageous effect at all. Some studies have even shown an increase in mortality among those who took supplementary vitamins. All in all, the free-radical theory of ageing should not be consigned completely to the realm of fairy tales, but it remains the case that there is no hard proof of the theory that ageing is simply caused by a lack of sufficient antioxidants in our bodies or our food.

INSULIN AND GROWTH HORMONE

The first results of experiments with nematode worms had a massive impact when they appeared in the nineteen-nineties. Nematodes normally live an average of twenty days in the lab, but after a minuscule alteration in their DNA the worms were able to live to twice that age. It was not only their average lifespan that increased to forty days; their maximum lifespan also rose, to more than fifty days. Soon after, other laboratories confirmed these original findings. Papers were also published detailing other, similar DNA manipulations that gave rise to a longer life expectancy. It led to the identification of a number of genes that interact with each other to form a ‘signalling pathway’ and determine the lifespan of nematode worms. When different worms were crossed with each other, creating diverse combinations of gene variants, their offspring were able to live between four and eight times longer. Until then, no one had ever dreamt that an animal’s lifespan could be influenced so strongly by just a handful of genes. This discovery led to a boom in scientific research.

The proximate explanation for this increased longevity was found in the fact that those genes regulate the worm’s dauer stage (see Chapter 1). Nematodes can take different forms, somewhat like caterpillars and butterflies, which are also different forms of the same species. In its dauer form, the nematode worm is long-lived, but cannot reproduce. The ultimate explanation for the nematodes’ longer lifespan is that they can enter their dauer stage when conditions are harsh. Not reproducing while they wait for the circumstances to change for the better is a strategy that increases each individual’s chance of survival, and increases the fitness of the species as a whole.

Scientists thought at first that this mechanism was exclusive to nematodes, and that their findings could not be extrapolated to other species. They were greatly surprised — again! — when they gradually managed to unravel the mechanism at the molecular level. The signalling pathway that provides the worms with a dauer form was not unique, and showed a high degree of similarity with insulin and growth hormone. These are signalling substances that are used by other organisms, mammals, and humans to regulate metabolism and development.

This similarity was thought to be an indication that the signalling pathway can have similar life-prolonging effects in higher organisms, and was gradually confirmed in the years that followed. First, it was shown that a reduced level of activity of insulin–growth-hormone signalling in fruit flies leads to smaller individuals with a longer lifespan. However, the effect turned out not to be restricted to insects. The genetic experiment was repeated on mice, and they also lived longer and were usually smaller when their insulin–growth-hormone signalling level was reduced. Now it is clear that the dauer signalling pathway is ‘evolutionarily conserved’, which means that the same biological mechanism is present in several species. However, its effect varies from species to species. It is large in nematodes, less so in fruit flies, and relatively small in mice; those animals saw their lifespan prolonged by approximately 50 per cent.

The question is, of course, what effect this mechanism has in humans. Insulin and growth hormones regulate growth and development in our species. They are involved in the metabolism of sugars and fats, and control energy storage in fatty tissue. These hormones influence a whole range of processes that are crucially important for life. But do insulin and growth hormone also influence longevity in humans?

The first indication that reduced growth-hormone signalling activity can be beneficial for humans came from observations of patients with a rare congenital defect known as Laron syndrome. This defect occurs particularly in families where the parents are related. On average, one child in every four will have the condition in affected families; if both parents are carriers, a child receives a mutated gene from each of them. The mother and father do not suffer from the condition themselves, since they have one functioning copy of the gene and one mutated copy — all humans carry two copies of each chromosome, except the Y-chromosome in men. The syndrome is caused by the fact that the molecule to which growth hormone binds is damaged, and the growth-hormone signal does not get through. Hence, affected children do not develop properly, both physically and mentally, and they remain small. It might be expected that the affected family members, with their disturbed development, would die early, but many have a reasonable life expectancy. It is particularly striking that people with Laron syndrome almost never get diabetes or cancer, which are precisely the conditions that typically plague us in old age. In this respect, these patients are probably somehow similar to long-lived dwarf mice or tiny Brandt’s bats, although those animals’ growth-hormone signal is disturbed at a different location. All indications are that animals which can get by on fewer growth hormones live longer, but are smaller than normal.

In Leiden, the research group led by Professor Eline Slagboom and myself investigated whether a genetically determined variation in insulin and growth hormone also affects the rate of ageing among the general population. We examined the genes connected with insulin and growth hormone in samples taken from people who had reached extreme old age. With the rapidly advancing possibilities for genetic analysis, we were able to detect subtle genetic differences among our 85-year-old subjects. These variations, which they had received from their parents thanks to the mechanism of sexual reproduction, can be seen on the biological level as the results of unintentional genetic experiments. Subjects who were carriers of one or more of these subtle variations that resulted in reduced insulin and growth-hormone signalling were smaller and had a lower mortality rate, just like worms, flies, and mice. Other researchers observed similar results in their studies of centenarian subjects.

This shows that the evolutionarily conserved mechanism that affects the lifespan of worms, flies, and mice is also active in humans. However, unlike genetic experiments carried out in the lab, natural genetic variation within the general population is small, and its effects are much more limited than they are in worms and flies.

In Leiden, where we have collected data on a large number of long-lived families, we have investigated whether those people were carriers of a genetic variation that results in less active insulin–growth-hormone signalling. We were not able to establish a direct link. This result did not come as a great surprise. In the course of our research, we had already established that the offspring of these long-lived families look exactly the same as their partners, whom we considered ‘normal’. They were just as tall and just as fat — that is, they were not smaller, as was the case with the long-lived worms, flies, and mice. But how does this negative finding among long-lived families relate to the positive findings among 85-year-olds? We think that the long-lived families are endowed with another — genetically determined — biological mechanism that enables them to lead longer and healthier lives than the average. There are apparently various signalling pathways — different proximate explanations — for the same beneficial effect on the condition of our bodies. Sometimes, it seems these signalling pathways do overlap and interlock. For example, we were able to show that the offspring of long-lived families are less likely to develop diabetes, and have lower blood-sugar levels and a better metabolism. Those are precisely the biochemical characteristics shown by long-lived mice in the lab.

It is noteworthy that less active insulin and growth-hormone signalling is generally associated with beneficial biological effects and a longer lifespan. Insulin and growth hormones are absolutely necessary for normal development and survival. However, there are clearly negative aspects to insulin and growth hormones when it comes to old age. This is another example of ‘antagonistic pleiotropy’ (see Chapter 6). Inflammation is a further example of this phenomenon, since an active immune system is good for survival, but can lead to undesirable side effects in old age. But we should not be surprised that our bodies are so badly adjusted to old age. After all, it is only the beginning of our life, the periods of development and adulthood, that have been optimised over countless generations of natural selection. In evolutionary terms, the end of our lives is something of an afterthought.

What we definitely should not do is to doggedly insist that everything should remain the same as it was in our young adulthood. We know that enhancing a low level of growth hormone in old age to raise it to the level at puberty does not lead to improvement. The muscle growth this promotes may result in a stronger-looking body, but there is no corresponding increase in muscle strength, and taking growth hormone throws the body’s sugar metabolism out of kilter. It may also very well be the case that using growth hormone increases the risk of cancer. A similar effect has already been proven conclusively for hormone-replacement therapy, when menopausal women’s oestrogen levels are artificially boosted to ‘normal’ levels.

Our bodies and brains are complex systems that will undoubtedly be able to be more fine-tuned in the near future — especially in old age. But little good can be expected from the supposed panaceas available now. A person does not remain healthy for longer by taking hormones, vitamins, amino acids, or minerals. They should only be taken when a serious deficiency of one of those substances is detected in the body.

SHOULD WE EAT LESS?

One theory of ageing that is rapidly gaining in popularity is that we can stay alive longer by eating less. While we used to have to face regular food shortages in our evolutionary past, advances in agriculture and animal farming in developed countries mean we now live with an abundance of food that is forced on us day and night. Shortened lives due to food scarcity have been replaced by disease and death from overeating. We have to try to avoid overeating and the resultant obesity by resisting the many temptations that surround us, by consuming fewer calories and burning more. We now burn far fewer calories than we used to, because we engage in far less physical exertion. In other words, our modern environment no longer fits with the set of biological tools we evolved with. There is no need to be emaciated, and particularly not in old age, but young and middle-aged people have the lowest risk of illness and death if they are in good physical shape, while older people have the best chance of survival if they are slightly chubby. It seems advantageous to have some (fat) reserves in old age, in case of an internal or external ‘attack’ in the form of illness or accidents. No one has (yet) come up with a better explanation for this phenomenon.

True proponents of eating less, incidentally, do not advocate chubbiness in later life; they dream of living longer by eating 20 to 30 per cent less than the recommended average calorie intake. This results in being underweight, constant hunger, and a heightened sensitivity to cold. People who follow this strict regimen claim it gives them a feeling of wellbeing.

The whole idea behind this so-called caloric restriction is based on laboratory experiments conducted on mice, which live longer when fed 30 per cent fewer calories. They demonstrably stay healthy for longer and die later than mice that are allowed to eat as much as they want. This effect was first described in the nineteen-thirties, and is one of the most studied mechanisms to counteract ageing.

Caloric restriction works not only for mice, but also for other test animals, including fruit flies. Although the beneficial effect has been demonstrated repeatedly and is an expression of a genuine biological mechanism, it does not work for all flies and all mice. For a large number of genetic variants, caloric restriction has no consequence, or may even have a life-shortening effect. This points towards a ‘nature-nurture’ phenomenon, since the effect of caloric restriction (nurture) depends on the test animals’ genetic traits (nature). It seems each genetic variant within one species has its own optimum calorie intake. If that is the case, too much food is bad, but so is too little. This has now been proven in experiments.

Of course, what we really want to know is how this applies to humans. Is it better to eat (far) less food than the recommended amount? The answer may be found in a long-term experiment with rhesus monkeys, a species that is closely related to us in evolutionary terms. In these experiments, the monkeys are randomly separated into two equally sized groups, one of which receives a normal amount of food, while the other is given only 70 per cent of that amount. (Only the number of ‘empty’ calories is restricted.) The food is all of the same quality, sometimes with added supplements to make sure the test monkeys do not suffer from deficiencies of vitamins and other essential nutrients. The experiment is being carried out by two separate institutions in the United States, each working independently. It has been going on for several decades, and the effects on life expectancy can now begin to be measured, because a considerable number of monkeys have now died, and the general risk of mortality can be estimated for each group.

So what are the results so far? The monkeys that have eaten calorie-restricted food over a long period of time look younger in appearance, have more energy, and are less likely to develop the diseases that are typical of ageing, such as diabetes. This suggests that the ageing process is slower in those animals. However, this does not (yet) appear to be reflected in their survival rates. When all causes of death are taken together, the monkeys on the caloric restriction regimen do not live demonstrably longer. The studies are still underway, and the final word has not yet been spoken. These unparalleled experiments will need more time to show their full potential.

The quest for the Holy Grail is not only a matter for mythical kings like Arthur. Many research scientists hope to find a magic elixir that will stop the ageing process. That is an unrealistic quest, however. The number of biological mechanisms that cause damage to accumulate — proximate explanations — is endless. This means that there is no single way to prevent ageing. Some researchers are now advocating a change of course, with more focus on finding new methods of repair and replacement — that is, more external intervention when the body fails from within. Such methods have already come a long way. We hardly bat an eyelid these days when someone gets a replacement lens in their eye, or a new hip. There is hope that medical technology will soon provide a solution to childhood diabetes, which is caused by a loss of the insulin-producing cells. The islets of Langerhans, the source of those cells, can now be replaced. As this shows, we are moving ahead, step by step.